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\begin{document}

\title{Adverse drug reactions in SARS-CoV-2 inpatients: a case-series with a
focus on drug-drug interactions}



\author[1]{Giada Crescioli}%
\author[2]{Valentina Brilli}%
\author[2]{Cecilia Lanzi}%
\author[3]{Andrea Burgalassi}%
\author[3]{Alessandra Ieri}%
\author[4]{Roberto Bonaiuti}%
\author[3]{Elias Romano}%
\author[3]{Rinaldo Innocenti}%
\author[4]{Guido Mannaioni}%
\author[5]{Alfredo Vannacci}%
\author[4]{Niccolò Lombardi}%
\affil[1]{University of Florence, Department of Neurosciences, Psychology, Drug Research and Child Health, Tuscan Regional Centre of Pharmacovigilance}%
\affil[2]{University Hospital Careggi}%
\affil[3]{Affiliation not available}%
\affil[4]{University of Florence}%
\affil[5]{Florence Universitu}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Background and aim: The search for early and emergency effective
treatments for COVID-19 infection may have led to loss of sight of
treatments safety. In addition, characteristics of drug-drug
interactions (DDIs)-related adverse drug reactions (ADRs) in COVID-19
patients have not yet been studied in depth. The aim of the present
case-series study is to describe clinical and pharmacological
characteristics of SARS-CoV-2 inpatients, focusing on ADRs, particularly
those related to DDIs. Methods: We evaluated all reports of COVID-19
medications-related ADRs collected within the COVID-19 Units of Careggi
University Hospital, Florence (Italy), between January 1st and 31st May
2020. Information regarding COVID-19 medications, patients' demographic
and clinical characteristics, concomitant drugs, ADRs description and
outcome, were collected. Each case was evaluated for the causality
assessment and to identify the presence of DDIs. Results: During the
study period, 23 Caucasian patients (56.5\% males, mean age 76.1 years)
experienced one or more ADRs. The majority of them were exposed to
polypharmacy and 17.4\% presented concomitant conditions. ADRs were
referred to cardiovascular, psychiatric and gastrointestinal disorders.
The most frequently reported preferred term was QT prolongation (mean QT
interval 496.1 msec). ADRs improved or resolved completely in 60.8\% of
cases. For all patients, a case-by-case evaluation revealed the presence
of one or more DDIs, especially those related to pharmacokinetic
interactions. Conclusions: Despite the small number of patients, our
evidence underline the clinical burden of DDIs in SARS-CoV-2 inpatients
and the risk of unexpected and uncommon psychiatric ADRs.%
\end{abstract}%



\sloppy


\textbf{1. Introduction}

Since the outbreak of COVID-19 epidemic, clinicians started a real
``gold rush'' to find the best therapeutic option among those currently
available for infectious and inflammatory diseases {[}1{]}. Waiting for
a vaccine, the study of COVID-19 clinical characteristics proved
effective in directing towards meaningful medical choices.

Three main stages represent COVID-19 infection clinical course. In the
first phase, the virus replicates within the host cells and patients may
experience symptoms as dry cough, fever, and general weakness and
malaise {[}2{]}. In the second phase, the progression of the disease is
characterised by the development of a bilateral interstitial pneumonia
and by morphological changes in host's lungs {[}3{]}. Respiratory
symptoms, which could be stable in the first phase of pneumonia, could
worsen, due to both direct effects of the virus and host's immune
response, leading to clinical instability and severe hypoxemia {[}4{]}.
Only in a limited number of cases (third phase), patients experience a
``cytokine storm'' and following hyper-inflammatory state, with local
and systemic consequences {[}5{]}. Among them, at the lung level,
arterial and venous vasculopathy, with thrombosis of the small vessels
and evolution towards serious and sometimes permanent lung lesions. A
progressive alteration of inflammatory and coagulation parameters, such
as C-reactive Protein (PCR), ferritin, pro-inflammatory cytokines,
consumption of clotting factors, and increased levels of the fragments
of fibrin degradation (D-dimer), have been observed {[}6, 7{]}.

In this complex scenario, therapeutic strategies have focused on viral
growth containment in the first and second phase of the disease, and on
inflammation and coagulation control, in the second and third phases
(\textbf{Table 1} ) {[}8{]}. When COVID-19 pandemic spread to Italy, the
Italian Medicines Agency (AIFA) approved the off-label use of the
antiviral combinations lopinavir/ritonavir and darunavir/cobicistat, the
use of antimalarials chloroquine and hydroxychloroquine (HCQ), the
antibiotic azithromycin, and the anticoagulant enoxaparin {[}9{]}.
Clinical experience also suggested the use of tocilizumab, a humanized
monoclonal antibody against interleukin (IL)-6 receptor {[}10{]}.

However, the search for early and emergency effective treatments for
COVID-19 infection may have led to loss of sight of treatments safety.
From the beginning of COVID-19 pandemic, concerns about HCQ efficacy and
safety raised {[}11{]} and subsequently AIFA suspended its use in
SARS-CoV-2 patients out of clinical trials on May 29\textsuperscript{th}
2020 {[}12{]}. Moreover, based on available evidence concerning the
efficacy and safety of fixed associations darunavir/cobicistat and
lopinavir/ritonavir, AIFA also suspended their use out of clinical
trials on July 17\textsuperscript{th} 2020 {[}13, 14{]}.

Prevalence of adverse drug reactions (ADRs) in COVID-19 patients has not
yet been deeply evaluated, but results from observational studies
suggest that its frequency could be high in this population {[}15{]}.
The majority of ADRs includes gastrointestinal and liver system
disorders. Nevertheless, potential harmful ADRs should be closely
monitored, and pharmacovigilance monitors', toxicologists' and clinical
pharmacologists' support in COVID-19 Units should be carefully
considered in order to better manage COVID-19 therapies {[}16{]}. In
particular, good quality information regarding drug-drug interactions
(DDIs)-related ADRs are still lacking.

In this context, the aim of the present case-series study is to describe
clinical and pharmacological characteristics of SARS-CoV-2 inpatients,
focusing on ADRs, particularly those related to DDIs.

\textbf{2. Methods}

In the present observational study, we considered and evaluated all
reports of suspected ADRs collected in the COVID-19 Units of Careggi
University Hospital, Florence (Italy), between January
1\textsuperscript{st} and 31\textsuperscript{st} May 2020. All suspected
ADRs were collected from the clinical charts after a consultation
performed by the Toxicology Unit on request of clinicians working in
COVID-19 Units.

Following the Italian pharmacovigilance legislation {[}17{]}, a
multidisciplinary team composed by experts in pharmacovigilance (GC, AV,
NL) and clinical toxicology (VB, CL, AB, AI, GM) provided their
consultation and filled out the specific report form {[}18, 19{]},
collecting information on: (1) patients' demographic characteristics
(age, gender, ethnic group); (2) patients' clinical status; (3)
suspected drugs and concomitant medications (for each one,
administration route, therapy duration, dosages, and therapeutic
indication were recorded); (4) ADRs description; (5) ADRs outcome
(improvement, complete resolution, unchanged or worsened event,
resolution with sequelae, death). A ``suspected drug'' is defined as a
drug which is potentially associated with the observed ADR, while a
``concomitant medication'' is a drug the patient is exposed to at the
time of ADR occurrence. A concomitant medication may not necessarily be
associated to the ADR.

For each case included in the analysis the experts performed a medical
evaluation in order to assess the causality relationship between the
suspected drugs and their related ADRs according to the Naranjo's scale
{[}20{]}. Moreover, each case was evaluated with the aim of identifying
the presence of DDIs, which may have contributed to ADRs. DDIs were
identified using two different validated tools: (1) the open access Drug
Interaction Checker {[}21{]}, and (2) the drug interaction software
Micromedex Drug-REAX System (Thomson Reuters Healthcare Inc., Greenwood
Village, Colorado, United States), available online with restricted
access. As reported in the Micromedex {[}22{]} and Drug Interaction
{[}21{]} tools, DDIs were classified as mild, moderate, or major,
depending on their clinical impact on patient.

Suspected drugs and concomitant medications were classified according to
the Anatomical Therapeutic Chemical (ATC) classification system. ADRs
description according to diagnosis and symptoms was coded using the
Medical Dictionary for Regulatory Activities (MedDRA) and organized by
Preferred Term (PT) {[}23, 24{]}.

Data are presented as number and percentages or, for continuous
variables, as mean and standard deviation (SD).

\textbf{3. Results}

Between January 1st and May 31st 2020, among patients hospitalised in
the COVID-19 Units of Careggi University Hospital, Florence (Italy),
clinicians requested a consultation for a total of 23 patients who
experienced one or more ADRs.

All patients were Caucasian with a mean age of 76.1 (SD \textbf{Table 2}
).

\textbf{Table 3} shows a case-by-case description of evaluated ADR
reports. One patient presented an elevation of transaminases, 3 patients
experienced gastrointestinal (GI) ADRs (nausea, diarrhoea, vomiting and
GI pain), 18 patients showed cardiovascular (CV) ADRs (ECG QT
prolongation), one patients presented a prolongation of the QT interval
along with symptoms of major depression, and one patient reported
psychotic symptoms. The 19 patients who experienced an ECG QT
prolongation, showed a mean prolongation of QT interval of 496.1 (SD
\selectlanguage{ngerman}±14.4) msec (\textbf{Table 2} ).

Table 4 shows all moderate and major DDIs observed in our sample between
COVID-19 treatments and patients' concomitant medications. The
application of tools for interactions revealed that all patients
presented at least one DDI. Among 82 different DDIs, 53 (64.4\%) were
moderate, and 32 (39\%) increased the risk of QT prolongation. Many
others DDIs (n=112) were identified between medications other than
COVID-19 treatments (\textbf{Supplementary Table 1} ).

\textbf{4. Discussion}

This study aimed to describe the clinical and pharmacological
characteristics of SARS-CoV-2 inpatients who experienced one or more
ADRs, with a focus on DDIs. Based on the evidence herein reported, the
majority of ADRs occurred in elderly patients exposed to polypharmacy.

\emph{Off-label} drug utilisation and DDIs are well known causes of ADRs
in the general population {[}2524{]}. In the case of COVID-19 pandemic,
lacking of specific pharmacological treatments forced clinicians and
regulatory agencies to resort to currently available drugs. Thus,
\emph{off-label} drug utilisation could not be avoided. On the contrary,
a patient's complete anamnesis, in particular regarding comorbidities
and concomitant medications, may help in avoiding the occurrence of
ADRs, often due to DDIs.

In our sample, according to the case-by-case clinical evaluation, most
frequently reported ADRs were Cardiac, Psychiatric and nervous system,
and Gastrointestinal and hepatic disorders.

Cardiac disorders

We observed 19 cases of CV ADRs, in particular ``QT prolongation''. In
these cases, the most frequently reported suspected COVID-19 medications
were HCQ, azithromycin, lopinavir/ritonavir and darunavir/cobicistat,
which are, based on their pharmacokinetic and pharmacodynamic
properties, commonly associated to CV events.

HCQ acute toxicity occurs most frequently when therapeutic or high doses
are administered rapidly through parenteral routes. HCQ doses of
\textgreater{}5 g given parenterally usually are fatal. Toxic
manifestations relate primarily to the CV system, including hypotension,
suppressed myocardial function, arrhythmias, and eventual cardiac
arrest. Due to its long elimination half-life (\textgreater{}40 days)
{[}26{]}, prolonged treatment with high doses may also cause ADRs such
as widening of the QRS interval, and T-wave abnormalities. In fact, it
is well known that HCQ inhibits human ether-a-go-go related gene (hERG)
potassium channels. Inhibition of hERG can block the outward flow of
potassium, which leads to intracellular accumulation of potassium and
ventricular repolarization and results in QT prolongation and torsade de
pointes (TdP) {[}27{]}. These complications usually disappear shortly
after the drug withdrawal. HCQ may also inhibit CYP2D6, interacting with
a variety of different COVID-19 and non-COVID-19 medications.

The macrolide azithromycin is a weak inhibitor of CYP3A4. In this case,
in connection with its effect on QT prolongation, the potential for DDIs
is associated to azithromycin pharmacodynamic characteristics. As such,
caution should always be observed when combining azithromycin with other
molecules that increase the QT interval, such as HCQ. In particular, QT
prolongation seems to be significantly higher in patients who received
the two medications concomitantly {[}28{]}. The exact mechanism by which
azithromycin and other macrolides prolong the QT interval is through a
blockade of the rapid component, IKr, of the delayed rectifier potassium
current IK, which is encoded by the hERG {[}29{]}, similarly to HCQ.

Special caution must be used when administering protease inhibitors,
such as lopinavir/ritonavir, due to their potential of inducing QT
interval prolongation, particularly when used in combination with other
pro-arrhythmic medications, such as HCQ and azithromycin. In fact,
lopinavir/ritonavir may increase concentrations of the co-administered
medicinal products and this may result in an increase of their
associated cardiac ADRs. This can be explained by the ability of
lopinavir/ritonavir to modulate enzymes, in particular CYP3A4 and
P-glycoprotein (P-gp). Lopinavir/ritonavir may also inhibit BCRP and
OATP1B1 transporters {[}30{]}. These pharmacokinetic characteristics
were also observed for darunavir/cobicistat {[}31{]}, leading to a
comparable profile in terms of DDIs and potentially related CV ADRs.

In general, attention should be exercised when COVID-19 treatments are
combined with drugs known to increase the PR or QT intervals, as they
also cause conduction and repolarization disorders by themselves.
Considering that QT prolongation could be an asymptomatic and
potentially fatal event, it should be always strictly monitored. The
risk factors for QT prolongation and TdS are female sex, older age,
heart disease, exposure to QT interval prolonging drugs or metabolic
inhibitors, bradycardia, and electrolyte disturbance {[}28{]}. The
cornerstone of the management of acquired QT prolongation includes the
identification and discontinuation of any suspected drug and the prompt
correction of any metabolic abnormalities {[}32{]}. Short-term treatment
includes the administration of intravenous magnesium sulphate and
potassium chloride to manage a possible hypomagnesemia or hypokalemia.
Thus, ECG and serum potassium levels should be frequently checked.

Psychiatric and nervous system disorders

We observed two cases of psychiatric disorders, in particular ``major
depression syndrome'' and ``psychotic crisis'', accompanied by
agitation, delirium, and aggressiveness. In these cases, the suspected
COVID-19 medications were HCQ, darunavir/cobicistat, and, for one
patient, tocilizumab. Considering the presence of co-administered
antidepressants, antipsychotics, and hypnotic and sedative agents, for
these patients a COVID-19 drugs-related reduction of the activity of
central nervous system medications could not be excluded. At the same
time, psychological and social distress linked to COVID-19 infection
should be taken into consideration {[}33, 34{]}. In fact, a recent
systematic review and meta-analysis confirmed that SARS-CoV-2 might
cause depression, anxiety, neuropsychiatric syndromes, and delirium in a
significant proportion of patients in the acute stage {[}35{]}. Of
notice, psychiatric ADRs are not commonly associated to HCQ {[}36{]},
darunavir/cobicistat {[}37{]}, and tocilizumab {[}38{]}.

Cases of episodes of manic behaviour with psychotic features,
persecutory delusions, anxiety, and reality detachment triggered by
chloroquine were described {[}39-43{]}. Considering that HCQ and
chloroquine have similar pharmacological properties, their toxicity
profiles could be considered comparable. A meta-analysis {[}44{]} and a
pharmacovigilance study on registry {[}45{]} confirmed the association
between HCQ and psychiatric events. The mechanisms responsible for the
psychiatric ADRs following HCQ exposure are not fully clarified. Among
proposed hypotheses, there are the cholinergic imbalance related to the
inhibition of acetylcholinesterase, prostaglandin E antagonism, the
accumulation of HCQ toxic metabolites in lysosomes, and the
down-regulation of Glycoprotein-P in the blood-brain barrier {[}46{]}.
Moreover, HCQ seems to inhibit the serotonin transporter, increasing its
levels in the synapsis, and to act as N-methyl-d-aspartate agonist and
\selectlanguage{greek}γ-\selectlanguage{english}aminobutyric acid antagonist {[}46{]}. In general, psychiatric ADRs
resolution follows HCQ withdrawal.

Among psychiatric ADRs, only ``abnormal dreams'' are reported in
darunavir/cobicistat summary of product characteristics (SPC) {[}37{]},
and, to date, literature is lacking evidence on this topic. In general,
protease inhibitors have limited central nervous system penetration and
therefore less-pronounced neurological and psychiatric ADRs {[}47{]}.
Among this group, ritonavir alone or in combination is more likely to
produce psychiatric ADRs, in particular mood changes, agitation, and
anxiety. In a clinical trial, HIV patients were randomized to
darunavir/ritonavir or darunavir/ritonavir in combination with two
nucleoside/nucleotide reverse transcriptase inhibitors {[}48{]}. After
48 weeks of therapy, grade 1-4 nervous system and psychiatric ADRs were
seen in 16\% and 9\% of patients in each treatment arm. Researchers
reported the following psychiatric manifestations: anxiety, depression,
obsessive-compulsive disorder, and psychotic crisis. Considering that
cobicistat is a CYP3A4 inhibitor and recommendations reported in its SPC
suggest reducing the dosages of concomitant central nervous system
medications, actually, there is no possibility of a drug therapeutic
failure of antipsychotics driven by the pharmacokinetic properties of
suspected protease inhibitors. Therefore, psychiatric ADRs observed in
our sample may have been mainly related to high-dose HCQ and to
underlying psychiatric comorbidities.

After a literature search, we ascertained the lack of evidence on
psychiatric ADRs related to tocilizumab {[}38{]}. Nowadays, the
association between tocilizumab and psychiatric ADRs cannot be fully
explained. As for protease inhibitors, particularly
darunavir/cobicistat, psychiatric ADRs may have been mainly related to
high-dose HCQ and to pre-existing psychiatric disorders.

When diagnosis of~a psychiatric ADRs is~made, the best solution is~to
discontinue any suspected drug. Based on our clinical experience,
depending on psychiatric clinical manifestation and on QT interval
values, the administration of specific antipsychotic medications (i.e.,
chlorpromazine) could be considered. Usually, patient's mental status
reverts to~normal in a few days. In case of emergencies, emotional
distress is ubiquitous, but some groups may be more vulnerable than
others. In particular, people at heightened risk for COVID-19, those who
contract the disease, and people with pre-existing medical or
psychiatric conditions are at increased risk for adverse psychosocial
outcomes {[}49{]}. Particular attention should also be given to mental
health of people in conditions of increased risk, such as women during
pregnancy {[}50{]} or post-partum {[}51{]}.

Gastrointestinal and hepatic disorders

We observed four cases of GI and hepatic disorders, in particular
``nausea'', ``vomiting'', ``diarrhoea'' and ``hypertransaminasemia''. In
these cases, all classes of COVID-19 medications were involved and GI
intolerance often led to pharmacological switching between the
associations lopinavir/ritonavir and darunavir/cobicistat. This kind of
non-specific ADRs is frequently (\emph{common} or \emph{very common} )
observed for all medication classes, including that of COVID-19
treatments {[}30, 36-38, 52{]}. The evaluation of causality assessment
for GI and hepatic disorders must take into consideration the presence
of concomitant medications and the underlying SARS-CoV-2 infection,
which is commonly associated with GI symptoms {[}53{]}.

\textbf{5. Conclusions}

Despite the small number of patients, the evidence reported in the
present analysis confirms that the clinical burden of DDIs in SARS-CoV-2
inpatients is relevant. Moreover, the risk of unexpected and uncommon
ADRs, such those referred to psychiatric disorders, was highlighted. In
this population, COVID-19 treatments should be used with extreme
caution, especially in fragile and polymedicated patients. Although
living in the context of a global emergency and looking for an effective
therapeutic treatment, drug safety should never be overlooked,
especially in the presence of DDIs.

\textbf{Acknowledgments}

All authors, Giada Crescioli, Valentina Brilli, Cecilia Lanzi, Andrea
Burgalassi, Alessandra Ieri, Roberto Bonaiuti, Elias Romano, Rinaldo
Innocenti, Guido Mannaioni, Alfredo Vannacci, and Niccol\selectlanguage{ngerman}ò Lombardi,
declare that they do not have any conflict of interest regarding this
publication. This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-profit sectors.

\textbf{Data Availability Statement}

Data will be available upon reasonable request.

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53. Lin L, Jiang X, Zhang Z, Huang S, Zhang Z, Fang Z, et al.
Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut.
2020 Jun;69(6):997-1001.

\textbf{Table 1.} Indication of use and mechanism of action of principal
SARS-CoV-2 medications in Italy.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{SARS-CoV-2} \textbf{infection phase}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{Medication}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{Indication}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{Mechanism of action}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{AIFA authorization}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{Phase I and II} Viral growth containment\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Darunavir/cobicistat Lopinavir/ritonavir\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
HIV treatment\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Inhibition of viral replication by the binding and inactivation of the
3CLpro and PL2pro proteases\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Off-label use restricted to RCTs\\
\emph{(last update July 17\textsuperscript{th} 2020)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Hydroxychloroquine Chloroquine\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Antimalarials, antirheumatics\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Increasing of endosomal pH crucial for virus-cell fusion\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Off-label use restricted to RCTs\\
\emph{(last update July 22\textsuperscript{th} 2020)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Remdesivir*\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Ebola virus\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
In vitro and in vivo activity against SARS-CoV-2, MERS-CoV and
SARS-CoV\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Compassionate use\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Ribavirin*\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Chronic HCV and RSV infections\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Guanosine analogue that interferes with the replication of RNA and DNA
viruses\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Compassionate use\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{Phase III} Inflammation and coagulation control\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Azithromycin\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Antibacterial for systemic use\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Downregulation of adhesion molecules of cell surface, reduction of
pro-inflammatory cytokines production\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Authorized out of RCTs only in SARS-CoV-2 positive adult patients with
bacterial infections\\
\emph{(last update May 5\textsuperscript{th} 2020)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Canakinumab*\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Arthritis, autoinflammatory fever, Still's disease (IL-1 \selectlanguage{greek}β
\selectlanguage{english}antibody)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reduction of SARS-CoV-2 induced pneumonia and inflammation\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Compassionate use\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Enoxaparin\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Prophylaxis of venous thromboembolism\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Containment of thrombotic phenomena from the pulmonary circulation\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Off-label use\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Tocilizumab\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
RA (IL-6 receptor antibody)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reduction of SARS-CoV-2 induced pneumonia and inflammation\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Off-label use\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Ruxolitinib*\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Myelofibrosis (inhibitor of JAK1 and JAK2 kinases)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Reduction of SARS-CoV-2 induced pneumonia and inflammation\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Compassionate use\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Solnatide*\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Pseudo-hypoaldosteronism 1B\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
In study to treat pulmonary permeability edema in Austria and
Germany\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Compassionate use\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

* Compassionate use. AIFA: Italian Medicines Agency; CoV: coronavirus;
HCV: hepatitis virus C; HIV: Human Immunodeficiency Viruses; MERS:
Middle East Respiratory Syndrome; RA: rheumatoid artritis; RCT:
randomized clinical trial; RSV: Respiratory syncytial virus; SARS:
Severe Acute Respiratory Syndrome.

\textbf{Table 2.} Patients' characteristics.\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Cases characteristics}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{No. of Cases} \textbf{N=23 (\%)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Patient age, years}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
19-64\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
4 (17.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
65-79\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
5 (21.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
14 (60.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Mean \selectlanguage{ngerman}± standard deviation\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
76.1\selectlanguage{ngerman}±14.40\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Gender}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
13 (56.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
10 (43.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{No. of suspected drugs}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
10 (43.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
8 (34.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
5 (21.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{No. of concomitant medications}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
None\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3 (13.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
1-5\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
4 (17.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
6-10\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
11 (47.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
5 (21.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{No. of concomitant conditions}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
None\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
5 (21.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
1-5\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
14 (60.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
4 (17.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Outcome}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
14 (60.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Death\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
5 (21.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Unchanged or worsened event\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
3 (13.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Complete resolution\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
1 (4.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{Causality assessment}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Certain\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Probable\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
17 (73.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Possible\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
6 (26.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Not classifiable\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\textbf{QT prolongation (19 patients), msec}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Mean \selectlanguage{ngerman}± standard deviation\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
496.1\selectlanguage{ngerman}±36.64\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textbf{Table 3.} Case-by-case clinical description of all evaluated
reports.\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Case}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Age (years)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{M/F}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Adverse Drug Reactions (PT)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Outcome}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Suspected drugs}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Concomitant medications}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Concomitant conditions}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
36\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Nausea, vomiting, abdominal pain, drug level modification\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Tacrolimus Darunavir/cobicistat\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
None\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Renal transplant\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
80\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged, atrial flutter, hemiplegia, hypokalaemia, major
depression\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Risperidone\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Sertraline, olanzapine, lorazepam, ceftriaxone, enoxaparin,
lopinavir/ritonavir*, darunavir/cobicistat*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
None\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
61\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hypertransaminasemia\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Lopinavir/ritonavir Darunavir/cobicistat Tocilizumab HCQ\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Azithromycin, bisoprolol, pantoprazole, enoxaparin, lorazepam,
atorvastatin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Atrial fibrillation\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
52\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Diarrhoea, vomiting\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Complete resolution\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Darunavir/cobicistat HCQ Azithromycin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
None\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
None\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
78\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged, hypokalaemia\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Lopinavir/ritonavir\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Darunavir/cobicistat*\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Cardiomyopathy and pacemaker\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
84\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged, vomiting\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Lopinavir/ritonavir Azithromycin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
None\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Pancreatic lesions\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
56\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Lopinavir/ritonavir Azithromycin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Darunavir/cobicistat*, enoxaparin, acetylsalicylic acid, candesartan,
losartan, betamethasone, amoxicillin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hypertension\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
93\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Citalopram\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Simvastatin, levothyroxine, bromazepam, trazodone, enoxaparin,
azithromycin, ceftriaxone\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
None\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
82\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Lopinavir/ritonavir Azithromycin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Sevelamer, pantoprazole, bisoprolol, furosemide, methylprednisolone,
piperacillin/tazobactam, linezolid, epoetin alpha\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Renal failure, anaemia, hypertension\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
80\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Unchanged event\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Sertraline Azithromycin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Valsartan, esomeprazole, pantoprazole, lorazepam, amlodipine,
mesalamine, tamsulosin, loperamide, piperacillin/tazobactam,
acetylsalicylic acid, enoxaparin, furosemide\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
None\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
67\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Unchanged event\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Lopinavir/ritonavir Azithromycin Haloperidol Levomepromazine
Zuclopenthixol\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Valproic acid, atorvastatin, lorazepam, fondaparinux\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Paranoid schizophrenia, hypercholesterolemia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
85\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Unchanged event\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Lopinavir/ritonavir HCQ\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Piperacillin/tazobactam, magnesium sulphate, linezolid, fluticasone
propionate/vilanterol, bisoprolol, pantoprazole, thiamazole,
allopurinol, acetylsalicylic acid, ursodeoxycholic acid, calcium
carbonate, calcitriol\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Renal failure, hyperthyroidism, BPH, heart failure\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
70\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Darunavir/cobicistat Azithromycin Amiodarone\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Warfarin, furosemide, potassium chloride, atorvastatin,
amoxicillin/clavulanate, acetaminophen, enoxaparin, ruxolitinib,
aclidinium bromide\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
COPD, hypothyroidism, atrial fibrillation, renal failure\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
86\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Lopinavir/ritonavir\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Furosemide, apixaban, atorvastatin, nitroglycerine, clonidine, potassium
chloride, darunavir/cobicistat*, enoxaparin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
None\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
93\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Lopinavir/ritonavir HCQ Azithromycin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Ceftriaxone, furosemide, bisoprolol, tamsulosin, dutasteride, ramipril,
enoxaparin, insulin, gliclazide, vildagliptin, metformin, perindopril,
barnidipine, simvastatin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Diabetes, hypertension, BPH, vascular encephalopathy, lower limbs
obliterating arteriopathy\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
16\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
80\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Lopinavir/ritonavir HCQ Azithromycin Haloperidol\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Verapamil, lansoprazole, acetylsalicylic acid, macrogol,
enoxaparin\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Alzheimer and Parkinson's diseases, hypertension, right carotid
stenosis, renal failure, hepatic steatosis\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
85\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged, hypokalaemia\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Magnesium sulphate\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Tamsulosin, bisoprolol, warfarin, atorvastatin, bicalutamide,
rabeprazole, meropenem, vancomycin, potassium chloride\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hypertension, hypercholesterolemia, neuropathic pain, prostatic cancer,
mitral valve intervention, hypokalaemia and hypomagnesemia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
18\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
71\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Darunavir/cobicistat\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Simvastatin, allopurinol, olmesartan, nebivolol, rivaroxaban, potassium
chloride\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hypertension, dyslipidaemia, atrial fibrillation, pulmonary emphysema,
obesity\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
19\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
89\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Initial improvement of QT prolongation and death\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Lopinavir/ritonavir HCQ Azithromycin Citalopram\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Pantoprazole, bisoprolol, clopidogrel, atorvastatin, quetiapine,
promazine, piperacilline/tazobactam, enoxaparin, olanzapine\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Mild mental retardation, Parkinson's disease, past severe head injury
with subdural hematoma, chronic dysphagia, thrombocytopenia, anaemia,
hypertension, dyslipidaemia, chronic renal failure\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
65\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Psychosis, agitation, delirium, aggressiveness\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Darunavir/cobicistat Tocilizumab\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Dutasteride, allopurinol, propofol, risperidone, valproic acid,
clonazepam, ramipril, amlodipine, midazolam, spironolactone,
dexmedetomidine, olanzapine\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Overweight, hyperuricemia, prostatic hypertrophy\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
81\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Darunavir/cobicistat\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Thiamazole, pantoprazole, folic acid, potassium chloride, bisoprolol,
furosemide, warfarin, potassium canrenoate, alprazolam, enoxaparin and
iron, vitamin C and vitamin B12 supplementation\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Atrial fibrillation, hypertension, hyperthyroidism, osteoporosis, mitral
valve disease\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
89\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Death\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Trazodone\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Ceftriaxone, methylprednisolone, acetylsalicylic acid,
acetaminophen/codeine, alprazolam, omeprazole, valproic acid, morphine,
enoxaparin, calcium and vitamin D3 supplementation\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Cognitive impairment, chronic subcortical vascular encephalopathy,
kidney heteroplasia, hypertension, osteoporosis, osteoarthritis,
anxiety-depressive syndrome\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
23\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
88\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ECG QT prolonged\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Improvement\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HCQ Darunavir/cobicistat Haloperidol\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Promazine, enoxaparin, potassium chloride\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Alzheimer's disease\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

BPH: benign prostatic hyperplasia; COPD: chronic obstructive pulmonary
disease; ECG: electrocardiogram; F: female; HCQ: hydroxychloroquine; M:
male.

* This medication was not administered simultaneously with the suspected
drugs. In particular, the patient was not exposed to this medication at
the time of ADR occurrence.

\textbf{Table 4.} Major and moderate drug-drug interactions between
COVID-19 treatments and patients' concomitant medications.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Interacting drugs} & \textbf{Interacting active principles} &
\textbf{Interaction severity} & \textbf{Interaction
effects}\tabularnewline
\textbf{COVID-19 medication with other COVID-19 therapies} &
HCQ-azithromycin & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& HCQ-lopinavir/ritonavir & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& HCQ-tocilizumab & Moderate & Increased risk of peripheral
neuropathy.\tabularnewline
& Lopinavir/ritonavir-azithromycin & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Lopinavir/ritonavir-darunavir/cobicistat & Moderate & Altered blood
levels and effects of both medications due to darunavir/cobicistat
inhibition and lopinavir inhibition or induction of CYP450
3A4.\tabularnewline
\textbf{COVID-19 medication with CNS medications} &
Azithromycin-citalopram & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& Azithromycin-haloperidol & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& Azithromycin-olanzapine & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Azithromycin-promazine & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Azithromycin-quetiapine & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Azithromycin-trazodone & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Darunavir/cobicistat-alprazolam & Moderate & Increased blood levels of
alprazolam due to darunavir/cobicistat inhibition of CYP450
3A4.\tabularnewline
& Darunavir/cobicistat-clonazepam & Moderate & Increased blood levels of
clonazepam due to darunavir/cobicistat inhibition of CYP450
3A4.\tabularnewline
& Darunavir/cobicistat-midazolam & Major & Increased blood levels of
midazolam due to darunavir/cobicistat inhibition of CYP450
3A4.\tabularnewline
& Darunavir/cobicistat-risperidone & Moderate & Increased blood levels
of risperidone to darunavir/cobicistat inhibition of CYP450
3A4.\tabularnewline
& Darunavir/cobicistat-sertraline & Moderate & Decreased blood levels
and effects of sertraline.\tabularnewline
& Enoxaparin-citalopram & Moderate & Increased risk of
bleeding.\tabularnewline
& Enoxaparin-sertraline & Moderate & Increased risk of
bleeding.\tabularnewline
& HCQ-citalopram & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& HCQ-codeine & Moderate & Increased risk of codeine reduced
efficacy.\tabularnewline
& HCQ-haloperidol & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& HCQ-olanzapine & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& HCQ-promazine & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& HCQ-quetiapine & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& HCQ-risperidone & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& HCQ-sertraline & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& HCQ-trazodone & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& Lopinavir/ritonavir-citalopram & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& Lopinavir/ritonavir-haloperidol & Major & Increased risk of QT ECG
prolongation and increased blood levels of haloperidol due to
lopinavir/ritonavir inhibition of CYP450 2D6.\tabularnewline
& Lopinavir/ritonavir-olanzapine & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Lopinavir/ritonavir-promazine & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Lopinavir/ritonavir-quetiapine & Major & Increased blood levels of
quetiapine due to lopinavir/ritonavir inhibition of CYP450 3A4 and
increased risk of QT ECG prolongation.\tabularnewline
& Lopinavir/ritonavir-risperidone & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Lopinavir/ritonavir-sertraline & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Lopinavir/ritonavir-valproic acid & Moderate & Reduced blood levels of
valproate due to lopinavir/ritonavir induction of
glucuronosyltransferases.\tabularnewline
& Tocilizumab-amlodipine & Moderate & Decreased blood levels of
amlodipine.\tabularnewline
& Tocilizumab-clonazepam & Moderate & Decreased blood levels of
clonazepam.\tabularnewline
& Tocilizumab-midazolam & Moderate & Decreased blood levels of
midazolam.\tabularnewline
\textbf{COVID-19 medication with CV medications} &
Azithromycin-atorvastatin or simvastatin & Moderate & Increased blood
levels of atorvastatin and increased risk of liver damage and myopathy
due to azithromycin inhibition of CYP450 3A4.\tabularnewline
& Azithromycin-sertraline & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Azithromycin-warfarin & Moderate & Increased risk of
bleeding.\tabularnewline
& Darunavir/cobicistat-amiodarone & Major & Increased risk of QT ECG
prolongation due to darunavir/cobicistat inhibition of CYP450
3A4.\tabularnewline
& Darunavir/cobicistat-amlodipine & Moderate & Increased blood levels of
amlodipine due to darunavir/cobicistat inhibition of CYP450
3A4.\tabularnewline
& Darunavir/cobicistat-apixaban & Major & Increased blood levels of
apixaban and increased risk of bleeding due to darunavir/cobicistat
inhibition of CYP450 3A4 and P-glycoprotein.\tabularnewline
& Darunavir/cobicistat-atorvastatin or simvastatin & Major & Increased
blood levels of atorvastatin and increased risk of liver damage and
myopathy due to darunavir/cobicistat inhibition of CYP450
3A4.\tabularnewline
& Darunavir/cobicistat-nebivolol & Moderate & Increased blood levels of
bisoprolol due to darunavir/cobicistat inhibition of CYP450
3A4.\tabularnewline
& Darunavir/cobicistat-rivaroxaban & Major & Increased blood levels of
rivaroxaban and increased risk of bleeding due to darunavir/cobicistat
inhibition of CYP450 3A4.\tabularnewline
& Darunavir/cobicistat-warfarin & Moderate & Altered blood levels of
warfarin.\tabularnewline
& Enoxaparin-amiodarone & Major & Increased risk of
bleeding.\tabularnewline
& Enoxaparin-apixaban & Major & Increased risk of
bleeding.\tabularnewline
& Enoxaparin-clopidogrel & Major & Increased risk of
bleeding.\tabularnewline
& Enoxaparin-losartan or valsartan & Moderate & Increased risk of
hyperkalaemia.\tabularnewline
& Enoxaparin-perindopril & Moderate & Increased risk of
hyperkalaemia.\tabularnewline
& Enoxaparin-warfarin & Major & Increased risk of
bleeding.\tabularnewline
& HCQ-amiodarone & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& HCQ-atorvastatin or simvastatin & Moderate & Increased risk of
peripheral neuropathy.\tabularnewline
& Lopinavir/ritonavir-apixaban & Major & Increased blood levels of
apixaban and increased risk of bleeding due to ritonavir
lopinavir/inhibition of CYP450 3A4 and P-glycoprotein.\tabularnewline
& Lopinavir/ritonavir-atorvastatin or simvastatin & Major & Increased
blood levels of atorvastatin and increased risk of liver damage and
myopathy due to lopinavir/ritonavir inhibition of CYP450
3A4.\tabularnewline
& Lopinavir/ritonavir-bisoprolol & Moderate & Increased risk of PR ECG
prolongation.\tabularnewline
& Lopinavir/ritonavir-verapamil & Moderate & Increased risk of
hypotension and of PR ECG prolongation.\tabularnewline
& Tocilizumab-atorvastatin & Moderate & Decreased levels of
atorvastatin.\tabularnewline
\textbf{COVID-19 medication with other medications} &
Azithromycin-loperamide & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Darunavir/cobicistat-betamethasone & Moderate & Increased blood levels
of betamethasone due to darunavir/cobicistat inhibition of CYP450
3A4.\tabularnewline
& Darunavir/cobicistat-clopidogrel & Major & Decreased efficacy of
clopidogrel due to darunavir/cobicistat inhibition of CYP450 3A4/5, 1A2,
2B6.\tabularnewline
& Darunavir/cobicistat-dutasteride & Moderate & Increased blood levels
of dutasteride.\tabularnewline
& Darunavir/cobicistat-ruxolitinib & Major & Increased blood levels of
ruxolitinib due to darunavir/cobicistat inhibition of CYP450
3A4.\tabularnewline
& HCQ-bicalutamide & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& HCQ-fluticasone propionate/vilanterol & Moderate & Increased risk of
QT ECG prolongation.\tabularnewline
& HCQ-gliclazide & Moderate & Increased risk of
hypoglycaemia.\tabularnewline
& HCQ-linezolid & Moderate & Increased risk of
neuropathy.\tabularnewline
& HCQ-loperamide & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Lopinavir/ritonavir-betamethasone & Moderate & Increased blood levels
of betamethasone due to lopinavir/ritonavir inhibition of CYP450
3A4.\tabularnewline
& Lopinavir/ritonavir-clopidogrel & Major & Decreased efficacy of
clopidogrel due to lopinavir/ritonavir inhibition of CYP450 3A4/5, 1A2,
2B6.\tabularnewline
& Lopinavir/ritonavir-dutasteride & Moderate & Increased blood levels of
dutasteride due to lopinavir/ritonavir inhibition of CYP450
3A4.\tabularnewline
& Lopinavir/ritonavir-fluticasone propionate/vilanterol & Major &
Increased exposure to fluticasone propionate and vilanterol due to
lopinavir/ritonavir inhibition of CYP450 3A4 and increased risk of QT
ECG prolongation.\tabularnewline
& Lopinavir/ritonavir-gliclazide & Moderate & Increased risk of
hyperglycaemia.\tabularnewline
& Lopinavir/ritonavir-insulin & Moderate & Increased risk of insulin
inefficacy.\tabularnewline
& Lopinavir/ritonavir-levothyroxine & Moderate & Reduced blood levels of
thyroxine due to lopinavir/ritonavir induction of
glucuronosyltransferase.\tabularnewline
& Lopinavir/ritonavir-metformin & Moderate & Increased risk of
hyperglycaemia.\tabularnewline
& Lopinavir/ritonavir-methylprednisolone & Major & Increased blood
levels of methylprednisolone due to lopinavir/ritonavir inhibition of
CYP450 3A4.\tabularnewline
& Lopinavir/ritonavir-tamsulosin & Major & Increased blood levels of
tamsulosin due to lopinavir/ritonavir inhibition of CYP450 3A4 and 2D6;
increased risk of hypotension and priapism.\tabularnewline
& Lopinavir/ritonavir-vildagliptin & Moderate & Increased risk of
hyperglycaemia.\tabularnewline
\bottomrule
\end{longtable}

CNS: central nervous system; CV: cardiovascular; ECG: electrocardiogram;
HCQ: hydroxychloroquine.

\textbf{Supplementary table 1} . Major and moderate DDIs between
concomitant medications reported in patients' anamnesis.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Interacting drugs} & \textbf{Interacting active principles} &
\textbf{Interaction severity} & \textbf{Interaction
effects}\tabularnewline
\textbf{CNS medications} & Alprazolam-codeine or morphine & Major &
Increased risk of CNS- and respiratory system depression.\tabularnewline
& Alprazolam-furosemide & Moderate & Increased risk of
hypotension.\tabularnewline
& Alprazolam-omeprazole & Moderate & Increased blood levels of
alprazolam.\tabularnewline
& Alprazolam-trazodone & Moderate & Increased risk of CNS- and
respiratory system depression.\tabularnewline
& Citalopram-promazine & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& Citalopram-quetiapine & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& Clonazepam-dexmedetomidine & Moderate & Increased risk of CNS- and
respiratory system depression.\tabularnewline
& Clonazepam-spironolactone & Moderate & Increased risk of
hypotension.\tabularnewline
& Clonazepam-propofol & Moderate & Increased risk of CNS- and
respiratory system depression.\tabularnewline
& Clonazepam-risperidone & Moderate & Increased risk of CNS- and
respiratory system depression.\tabularnewline
& Codeine-morphine & Major & Increased risk of CNS- and respiratory
system depression.\tabularnewline
& Codeine-trazodone & Moderate & Increased risk of serotonin
syndrome.\tabularnewline
& Codeine-valproic acid & Moderate & Increased risk of CNS- and
respiratory system depression.\tabularnewline
& Dexmedetomidine-amlodipine & Moderate & Increased risk of
hypotension.\tabularnewline
& Dexmedetomidine-midazolam & Moderate & Increased risk of CNS- and
respiratory system depression.\tabularnewline
& Dexmedetomidine-olanzapine & Moderate & Increased risk of CNS- and
respiratory system depression.\tabularnewline
& Dexmedetomidine-propofol & Moderate & Increased risk of CNS- and
respiratory system depression.\tabularnewline
& Dexmedetomidine-ramipril & Moderate & Increased risk of
hypotension.\tabularnewline
& Dexmedetomidine-risperidone & Moderate & Increased risk of CNS- and
respiratory system depression.\tabularnewline
& Dexmedetomidine-spironolactone & Moderate & Increased risk of
hypotension.\tabularnewline
& Haloperidol-verapamil & Moderate & Increased risk of
hypotension.\tabularnewline
& Lorazepam-bisoprolol & Moderate & Increased risk of
hypotension.\tabularnewline
& Lorazepam-furosemide & Moderate & Increased risk of
hypotension.\tabularnewline
& Lorazepam-haloperidol & Moderate & Increased risk of CNS- and/or
respiratory-depressant effects.\tabularnewline
& Lorazepam-olanzapine & Major & Increased CNS- and CV-depressant
effects (i.e., low blood pressure, weak pulse, muscle weakness,
drowsiness, and dizziness).\tabularnewline
& Lorazepam-risperidone & Moderate & Increased CNS- and/or
respiratory-depressant effects may be additively or
synergistically.\tabularnewline
& Lorazepam-tamsulosin & Moderate & Increased risk of
hypotension.\tabularnewline
& Midazolam-propofol & Moderate & Increased risk of CNS- and respiratory
system depression.\tabularnewline
& Midazolam-spironolactone & Moderate & Increased risk of
hypotension.\tabularnewline
& Morphine-trazodone & Moderate & Increased risk of CNS- and respiratory
system depression.\tabularnewline
& Olanzapine-amlodipine & Moderate & Increased risk of
hypotension.\tabularnewline
& Olanzapine-bisoprolol & Moderate & Increased risk of
hypotension.\tabularnewline
& Olanzapine-citalopram & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Olanzapine-clonazepam & Major & Increased risk of CNS
depression.\tabularnewline
& Olanzapine-midazolam & Major & Increased risk of CNS
depression.\tabularnewline
& Olanzapine-promazine & Moderate & Increased risk of paralytic ileus,
hyperthermia, heat stroke, and anticholinergic intoxication
syndrome.\tabularnewline
& Olanzapine-propofol & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Olanzapine-quetiapine & Moderate & Increased risk of paralytic ileus,
hyperthermia, heat stroke, and anticholinergic intoxication
syndrome.\tabularnewline
& Olanzapine-spironolactone & Moderate & Increased risk of
hypotension.\tabularnewline
& Promazine-bisoprolol & Moderate & Increased risk of
hypotension.\tabularnewline
& Promazine-quetiapine & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Quetiapine-bisoprolol & Moderate & Increased risk of
hypotension.\tabularnewline
& Risperidone-amlodipine & Moderate & Increased risk of
hypotension.\tabularnewline
& Risperidone-olanzapine & Moderate & Increased risk of paralytic ileus,
hyperthermia, heat stroke, and anticholinergic intoxication
syndrome.\tabularnewline
& Risperidone-midazolam & Moderate & Increased risk of CNS- and
respiratory system depression\tabularnewline
& Risperidone-propofol & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Risperidone-spironolactone & Moderate & Increased risk of
hypotension.\tabularnewline
& Sertraline-furosemide & Moderate & Increased risk of
hyponatraemia.\tabularnewline
& Sertraline-loperamide & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Sertraline-lorazepam & Moderate & Increased CNS- and/or
respiratory-depressant effects may be additively or
synergistically.\tabularnewline
& Sertraline-olanzapine & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Sertraline-risperidone & Moderate & Increased risk of QT ECG
prolongation.\tabularnewline
& Sertraline-tamsulosin & Moderate & Increased blood levels of
tamsulosin due to sertraline inhibition of CYP450 3A4 and/or 2D6 and
increased risk of hypotension.\tabularnewline
& Trazodone-citalopram & Major & Increased risk of serotonin syndrome
and of QT ECG prolongation.\tabularnewline
& Valproic acid-clonazepam & Moderate & Increased risk of drowsiness and
seizures.\tabularnewline
& Valproic acid-haloperidol & Moderate & Increased risk of CNS- and/or
respiratory-depressant effects.\tabularnewline
& Valproic acid-dexmedetomidine & Moderate & Increased risk of CNS-
and/or respiratory-depressant effects.\tabularnewline
& Valproic acid-morphine & Moderate & Increased risk of CNS-depressant
effects.\tabularnewline
& Valproic acid-olanzapine & Moderate & Increased risk of hepatic
toxicity.\tabularnewline
& Valproic acid-propofol & Moderate & Increased blood levels of
propofol.\tabularnewline
& Valproic acid-risperidone & Moderate & Increased blood levels of
valproic acid.\tabularnewline
& Valproic acid-trazodone & Moderate & Increased risk of CNS- and/or
respiratory-depressant effects.\tabularnewline
\textbf{CV medications} & Acetylsalicylic acid-amlodipine & Moderate &
Increased risk of hypertension.\tabularnewline
& Acetylsalicylic acid-enoxaparin & Major & Increased risk of
bleeding.\tabularnewline
& Acetylsalicylic acid-betamethasone or methylprednisolone & Moderate &
Reduced serum concentrations and therapeutic effects of
salicylates.\tabularnewline
& Acetylsalicylic acid-candesartan & Moderate & Increased risk of
candesartan inefficacy due to acetylsalicylic acid-related inhibition of
renal prostaglandin synthesis.\tabularnewline
& Acetylsalicylic acid-citalopram & Moderate & Increased risk of
bleeding.\tabularnewline
& Acetylsalicylic acid-losartan or valsartan & Moderate & Increased risk
of losartan inefficacy due to acetylsalicylic acid-related inhibition of
renal prostaglandin synthesis.\tabularnewline
& Acetylsalicylic acid-sertraline & Moderate & Increased risk of
bleeding.\tabularnewline
& Acetylsalicylic acid-verapamil & Moderate & Increased blood levels of
valproic acid.\tabularnewline
& Acetylsalicylic acid-verapamil & Moderate & Increased risk of
bleeding, bruising, headache, dizziness, weakness.\tabularnewline
& Amiodarone-furosemide & Major & Increased risk of QT ECG
prolongation.\tabularnewline
& Amiodarone-warfarin & Major & Increased risk of
bleeding.\tabularnewline
& Atorvastatin-amiodarone & Moderate & Increased blood levels of
atorvastatin and increased risk of myopathy.\tabularnewline
& Atorvastatin-bicalutamide & Moderate & Increased blood levels of
atorvastatin and increased risk of myopathy.\tabularnewline
& Atorvastatin-pantoprazole & Moderate & Increased blood levels of
atorvastatin and increased risk of liver damage and myopathy due to
competitive inhibition of intestinal P-glycoprotein and CYP450
3A4.\tabularnewline
& Bisoprolol-alprazolam & Moderate & Increased risk of
hypotension.\tabularnewline
& Bisoprolol-gliclazide & Moderate & Increased risk of
hypoglycaemia.\tabularnewline
& Bisoprolol-furosemide & Moderate & Increased risk of hyperglycaemia
and hypertriglyceridemia.\tabularnewline
& Bisoprolol-linezolid & Moderate & Increased risk of hypotension,
orthostasis, bradycardia, and heart failure.\tabularnewline
& Bisoprolol-methylprednisolone & Moderate & Increased risk of
bisoprolol inefficacy due to corticosteroids-related sodium and fluid
retention.\tabularnewline
& Candesartan-enoxaparin & Moderate & Increased risk of
hyperkalaemia.\tabularnewline
& Candesartan-betamethasone & Moderate & Increased risk of candesartan
inefficacy due to corticosteroids-related sodium and fluid
retention.\tabularnewline
& Clopidogrel-atorvastatin & Moderate & Decreased efficacy of
clopidogrel due to a mechanism of competitive inhibition of CYP450
3A4.\tabularnewline
& Clopidogrel-citalopram & Moderate & Increased risk of
bleeding.\tabularnewline
& Losartan-betamethasone & Moderate & Increased risk of losartan
inefficacy due to corticosteroids-related sodium and fluid
retention.\tabularnewline
& Olmesartan-potassium chloride & Major & Increased risk of
hyperkalaemia.\tabularnewline
& Perindopril-furosemide & Moderate & Increased risk of hypotension and
hypovolemia.\tabularnewline
& Perindopril-glicazide & Moderate & Increased risk of
hypoglycaemia.\tabularnewline
& Perindopril-insulin & Moderate & Increased risk of
hypoglycaemia.\tabularnewline
& Perindopril-metformin & Moderate & Increased risk of
hypoglycaemia.\tabularnewline
& Perindopril-vildagliptin & Moderate & Increased risk of
angioedema.\tabularnewline
& Ramipril-allopurinol & Major & Increased risk of severe
hypersensitivity reactions, neutropenia, agranulocytosis, and serious
infections.\tabularnewline
& Ramipril-clonazepam & Moderate & Increased risk of
hypotension.\tabularnewline
& Ramipril-olanzapine & Moderate & Increased risk of
hypotension.\tabularnewline
& Ramipril-risperidone & Moderate & Increased risk of
hypotension.\tabularnewline
& Ramipril-spironolactone & Major & Increased risk of
hyperkalaemia.\tabularnewline
& Ramipril-vildagliptin & Moderate & Increased risk of
angioedema.\tabularnewline
& Warfarin-amoxicillin/clavulanate & Moderate & Increased risk of
bleeding.\tabularnewline
& Warfarin-rabeprazole or pantoprazole & Moderate & Increased risk of
bleeding.\tabularnewline
\textbf{Other interactions} & Fluticasone
propionate/vilanterol-linezolid & Moderate & Increased risk of
hypertension, palpitation, tachycardia, and chest pain.\tabularnewline
& Furosemide-ceftriaxone & Moderate & Increased risk of
nephrotoxicity.\tabularnewline
& Furosemide-gliclazide & Moderate & Increased risk of
hyperglycaemia.\tabularnewline
& Furosemide-insulin & Moderate & Increased risk of
hyperglycaemia.\tabularnewline
& Furosemide-linezolid & Moderate & Increased risk of hypotension and
orthostasis.\tabularnewline
& Furosemide-methylprednisolone & Moderate & Increased risk of
hypokalaemia.\tabularnewline
& Furosemide-pantoprazole or esomeprazole & Moderate & Increased risk of
hypomagnesemia.\tabularnewline
& Furosemide-vildagliptin & Moderate & Increased risk of
hyperglycaemia.\tabularnewline
& Gliclazide-furosemide & Moderate & Increased risk of
hyperglycaemia.\tabularnewline
& Insulin-gliclazide & Moderate & Increased risk of
hypoglycaemia.\tabularnewline
& Insulin-vildagliptin & Moderate & Increased risk of
hypoglycaemia.\tabularnewline
& Vildagliptin-gliclazide & Moderate & Increased risk of
hypoglycaemia.\tabularnewline
\bottomrule
\end{longtable}

CNS: central nervous system; CV: cardiovascular; ECG: electrocardiogram.

\selectlanguage{english}
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\end{document}

