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\begin{document}

\title{Real-world experience of selexipag titration in pulmonary arterial
hypertension}



\author[1]{Sarah Cullivan}%
\author[1]{Ciara McCormack}%
\author[1]{Anandan Natarajan}%
\author[1]{Sean Gaine}%
\author[1]{Brian McCullagh}%
\affil[1]{Mater Misericordiae University Hospital}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Selexipag is an oral selective prostacyclin receptor agonist, that was
approved for use in patients with NYHA functional class II-III pulmonary
arterial hypertension (PAH). In the GRIPHON study, selexipag
demonstrated consistent efficacy for individualised doses in low, medium
and high dose stratums. In order to better understand the real world
approach to selexipag titration and to establish the individualised
maintenance regimens used in our centre, we performed this retrospective
study of the first 20 patients prescribed selexipag. Baseline
characteristics differed from the GRIPHON study, with more combination
therapy and comorbidities at baseline; however. Maintenance doses were
stratified as low-dose in 10\% (n=2), medium-dose in 70\% (n=14) and
high-dose in 20\% (n=4). Furthermore, two of these patients were
successfully transitioned from inhaled iloprost. This study demonstrates
that selexipag can be safely initiated, titrated and transitioned in an
outpatient setting to achieve an individualised dosing regimen.%
\end{abstract}%



\sloppy


\textbf{Real-world experience of selexipag titration in pulmonary
arterial hypertension}

\textbf{Data availability statement:}

Data available on request from the authors

\textbf{Abstract:}

Selexipag is an oral selective prostacyclin receptor agonist, that was
approved for use in patients with NYHA functional class II-III pulmonary
arterial hypertension (PAH). In the GRIPHON study, selexipag
demonstrated consistent efficacy for individualised doses in low, medium
and high dose stratums. In order to better understand the real world
approach to selexipag titration and to establish the individualised
maintenance regimens used in our centre, we performed this retrospective
study of the first 20 patients prescribed selexipag. Baseline
characteristics differed from the GRIPHON study, with more combination
therapy and comorbidities at baseline; however. Maintenance doses were
stratified as low-dose in 10\% (n=2), medium-dose in 70\% (n=14) and
high-dose in 20\% (n=4). Furthermore, two of these patients were
successfully transitioned from inhaled iloprost. This study demonstrates
that selexipag can be safely initiated, titrated and transitioned in an
outpatient setting to achieve an individualised dosing regimen.

\textbf{Introduction} :

Pulmonary arterial hypertension (PAH) is a devastating disease
characterised by irreversible pulmonary vascular proliferation and
remodelling resulting ultimately in right heart failure. Current therapy
targets the nitric oxide, endothelin and prostacyclin pathways to
promote pulmonary vasodilatation and reduce right ventricular
afterload.\textsuperscript{1, 2} Selexipag is an oral selective
prostacyclin receptor agonist that is used in the treatment of PAH. In
the GRIPHON trial the optimum dose of selexipag for maximum therapeutic
benefit was determined to be the maximum tolerated dose for each
individual patient. It is postulated that the dose differs between
patients due to variations in prostacyclin (IP) receptor expression and
density.\textsuperscript{3-5} The initiation dose of 200\selectlanguage{greek}μ\selectlanguage{english}g twice daily
is prescribed and titrated weekly until a total daily dose of 3200\selectlanguage{greek}μ\selectlanguage{english}g is
achieved or side effects become intolerable and an individual maximum
tolerated dose is established. In the GRIPHON study this strategy
demonstrated consistent efficacy for patients receiving low, medium or
high selexipag doses.\textsuperscript{6} In clinical trials selexipag
demonstrated improvements in six minute walk distance (6MWD), n-terminal
pro--brain natriuretic peptide (NT-proBNP), cardiac index (CI) and
pulmonary vascular resistance (PVR), and a significant reduction was
noted in the composite morbidity and mortality endpoint at a median of
70.7 weeks of treatment.\textsuperscript{6, 7} In order to better
understand the real world approach to selexipag titration we performed a
retrospective analysis of the clinical and treatment characteristics of
the first 20 patients prescribed selexipag in our centre.

\textbf{Aim} :

To perform a retrospective analysis of the clinical and treatment
characteristics of the first 20 patients prescribed selexipag in our
centre, with specific reference to drug titration and individualised
maintenance doses.

\textbf{Materials and Methods} :

This study received ethical approval from the institutional ethical
review board (IRB:1/378/2179 TMR). A retrospective search of the
hospital database was performed to identify patients with confirmed PAH
who commenced selexipag therapy, outside of a clinical trial, up until
June 2020. Paper charts and the hospital information technology service
(PatientCentre) were used to collect data that was subsequently fully
anonymised. Patients were excluded if they were commenced on selexipag
therapy in the context of a clinical trial, as their experience might
not reflect `real world' practice.

Data regarding patient demographics, PAH subtype, duration of PAH
diagnosis, co-morbidities and regular medications were collected
retrospectively. New York Heart Associated (NYHA) functional class (FC),
patient risk stratification category (using the 2015 ESC/ERS PAH
guidelines risk table) and 6MWD were also recorded.\textsuperscript{2}.
Details regarding selexipag indication, titration, maintenance doses,
reported side effects and compliance were also recorded from patient
records.

Statistical analysis was performed using GraphPad online statistical
software. Fisher's exact test was employed to assess the statistical
significance for categorical variables and t-test was used to calculate
significance between means. A value \textless{} 0.05 was considered
statistically significant (P \textless{} 0.05).

\textbf{Results} :

\textbf{Patient selection}

The first 20 patients prescribed selexipag in our centre, outside the
setting of a clinical trial, were included in this analysis.

\textbf{Baseline characteristics}

Of the 20 patients, 65\% (n=13) were female, the mean age was 55 \selectlanguage{ngerman}± 17
years, and 60\% (n=12) had a diagnosis of Idiopathic PAH (IPAH), 30\%
(n=6) PAH associated with connective tissue disease (CTD-PAH) and
10\%(n=2) were defined as other. Patients reported NYHA FC II symptoms
in 50\% (n=10) and FC III in 50\% (n=10) at baseline. Baseline risk
assessment was stratified as low in 25\% (n=5), intermediate in 65\%
(n=13) and high risk in 10\% (n=2). Dual combination therapy was
prescribed in 90\% (n=18) and triple combination therapy consisting of
inhaled iloprost in 10\% (n=2). Co-morbidities and additional baseline
medications were common and are displayed in \textbf{Table 1} .

\textbf{Selexipag dosing}

Selexipag was commenced at 200 \selectlanguage{greek}μ\selectlanguage{english}g twice daily, following the protocol
used in the GRIPHON study, increasing by 200 \selectlanguage{greek}μ\selectlanguage{english}g twice daily every seven
days if side effects were tolerable.\textsuperscript{6} The mean time to
reach an individual maintenance dose was 67 days (\selectlanguage{ngerman}± 26) and the mean
total daily maintenance dose was 1830 \selectlanguage{greek}μ\selectlanguage{english}g (\selectlanguage{ngerman}± 548) at the end of the
titration period. (\textbf{Table 2} ). Maintenance doses were stratified
as low-dose in 10\% (n=2), medium-dose in 70\% (n=14) and high-dose in
20\% (n=4). (\textbf{Table 3} ) Selexipag doses were reviewed at 6
months post initiation to ascertain if there were any subsequent dose
titrations. These were not significantly different from individual
maintenance doses established at the end of the titration period
(p=0.699). (\textbf{Table 2} )

\textbf{Transitioning between prostacyclin therapies}

Two patients were prescribed triple combination therapy at baseline,
including inhaled iloprost at doses of 5 \selectlanguage{greek}μ\selectlanguage{english}g six times a day. In both
cases when selexipag was initiated at 200 \selectlanguage{greek}μ\selectlanguage{english}g twice daily, iloprost was
simultaneously reduced to 5 \selectlanguage{greek}μ\selectlanguage{english}g four times a day by excluding the morning
and the evening iloprost doses. Iloprost was then reduced to 5 \selectlanguage{greek}μ\selectlanguage{english}g twice
daily in the second week, when selexipag was increased to 400 \selectlanguage{greek}μ\selectlanguage{english}g twice
daily. This was well tolerated and inhaled iloprost was discontinued by
week 3, with ongoing up titration of selexipag until individual
maintenance doses were achieved. Final doses of 1200 \selectlanguage{greek}μ\selectlanguage{english}g twice daily and
1400 \selectlanguage{greek}μ\selectlanguage{english}g twice daily were achieved in these cases, which was
significantly higher when compared to doses achieved by other patients
in our centre. (p=0.037)

\textbf{Side effects and tolerance}

All patients reported side effects during selexipag titration. The most
frequent reported side effects were nausea, gastroesophageal reflux
(GERD) and vomiting in 65\% (n=13), diarrhoea (65\%, n=13) and headache
in 65\% (n=13). Jaw discomfort occurred in 45\% (n=9). Clinical
worsening occurred in 1 case, in a patient with CTD-PAH with FC III
symptoms and high risk features at baseline, and required hospital
admission for treatment of right heart failure. (\textbf{Table 4} ) No
patients discontinued selexipag due to side effects or adverse events
and there were no reported deaths. There was one reported case of new
thyroid dysfunction (defined as subclinical hyperthyroidism).

\textbf{Discussion} :

The discovery of prostacyclin in 1976 and subsequent development of
synthetic analogues revolutionised the field of PAH.\textsuperscript{8,
9} These analogues include epoprostenol, iloprost and treprostinil,
which target IP receptors to stimulate adenylate cyclase, increase
cyclic adenosine monophosphate and promote beneficial downstream effects
including pulmonary vasodilatation. Interestingly, these agents are not
specific for the IP receptor and bind additional prostaglandin receptors
that have diverse functions.\textsuperscript{1, 10} Selexipag differs
from these analogues, as it is structurally distinct from prostacyclin
and is a selective agonist of the IP receptor.\textsuperscript{6} In our
centre, patients initiated on selexipag were more likely to be older
(mean age 54\selectlanguage{ngerman}± 16), with co-morbidities and additional baseline
medications, when compared to patients included in the GRIPHON study.
Additionally all patients were already on double combination therapy
(90\%, n=18) or triple therapy (10\%, n=2) at baseline, reflective of
current international best practice. These treatment characteristics
emphasise the importance of clear guidelines on drug initiation and a
standardised approach to transitioning between prostacyclin agents, as
this is increasingly encountered in clinical
practice.\textsuperscript{11-17}

The TRANSIT-1 study was an open-label phase IIIb study that
prospectively enrolled 34 patients with clinically stable PAH and
assessed the transition from inhaled treprostinil to oral
selexipag.\textsuperscript{15} Dose reductions were implemented at the
discretion of the investigators, highlighting that even in a controlled
environment there can be considerable variability in titration
approaches due to individual patient factors, including baseline
prostacyclin requirements and reported side effects. In our centre two
patients were transitioned from inhaled iloprost to oral selexipag.
There is a paucity of published data limited to a case reports detailing
the transition of iloprost to selexipag. \textsuperscript{18} Iloprost
is a stable analogue of prostacyclin, that can be administered via
nebulisation six to nine times a day to preferentially vasodilate
well-ventilated lung, with effects lasting 30 to 90
minutes.\textsuperscript{19} Aerosolised iloprost is generally well
tolerated as it typically avoids the systemic side effects of IV,
subcutaneous or oral routes of prostacyclin administration, however
there is some evidence that the cessation of iloprost overnight is
associated with a deterioration in hemodynamic
parameters.\textsuperscript{20} In our cohort two patients transitioned
from inhaled iloprost by reducing the frequency of drug administration,
rather than reducing the dose administered or duration of treatment
sessions. This method was well tolerated, with complete drug cessation
by week 3 in both cases. The final selexipag doses achieved in these two
cases were significantly higher than those achieved by patients who were
prostacyclin naïve, which one could speculate reflects iloprost
associated IP receptor desensitisation or a higher tolerance of
prostacyclin.

Any changes to baseline PAH therapy, including the initiation of oral
prostacyclin therapy, should involve careful patient selection and
multiparametric risk assessment.\textsuperscript{2} All patients
selected for selexipag therapy in this study were prevalent patients,
with a mean time since diagnosis of 4 years, which may have implications
for treatment response, as a post hoc analysis of patients included in
the GRIPHON study demonstrated more pronounced treatment effects in
patients who initiated therapy closer to their PAH
diagnosis.\textsuperscript{21} The importance of patient selection,
individual assessment and consideration of hemodynamic parameters was
highlighted by Yanaka et al in a study of 8 patients transitioned from
IV epoprostenol to oral selexipag.\textsuperscript{16} At evaluation
approximately 4.4 months post selexipag transitioning, there was a
significant reduction in cardiac index in these
patients.\textsuperscript{22} To address the knowledge gaps surrounding
patient selection for oral prostacyclin therapy, an expert consensus
statement on the treatment of PAH with oral prostacyclin agents was
published.\textsuperscript{23} This suggested 13 specific situations
where oral selexipag may be suitable, with reference to patients with
IPAH and CTD-PAH, with NYHA FC II-III and associated low to intermediate
risk features. Parenteral prostacyclin was recommended for patients with
high-risk hemodynamics or with NYHA FC IV symptoms.

Selexipag initiation was accompanied by extensive patient education of
anticipated side effects during the titration period and comprehensive
supervision by experienced PH nurse specialists who were familiar with
individual patients. Individual maintenance doses were established by 67
days on average. In our study the majority of patients (73\%, n=16)
achieved maintenance doses in the medium-dose stratum, with fewer
individual maintenance doses categorized in the high-dose stratum when
compared to the GRIPHON study. This is likely multifactorial in nature
and reflects differences in patient demographics and baseline
characteristics, including older age, more comorbidities and additional
baseline medications in our cohort. Prostacyclin-type side effects are
common and led to drug discontinuation in twice as many participants
when compared to placebo in the GRIPHON study.\textsuperscript{6}
Interestingly there were no cases of drug discontinuation in our cohort.
Interestingly selexipag does not appear to lead to IP receptor
desensitization over time, potentially due to partial antagonism of the
IP receptor, and therefore future titrations are generally not be
required once a maintenance dose is established.\textsuperscript{24, 25}
In our cohort, there was no significant difference between maintenance
doses at the end of the titration period and doses at 6 months post drug
initiation; however this is a relatively short interval and extended
follow-up would be required to support this.

Important limitations of this study include its retrospective
descriptive nature and the absence of long-term follow up. Due to the
COVID-19 pandemic a considerable proportion of clinical assessments were
performed using telemedicine technology and therefore hemodynamic data
was not included. Nevertheless this study reflects `real-world'
experience of selexipag and helps to highlight appropriate patient
selection for oral prostacyclin therapy and an approach to transitioning
between prostacyclin agents. Additionally as selexipag titration was
safely performed in an outpatient setting, guided by experienced PAH
nurse specialists, this has important implications for resource
utilisation and patient autonomy.

\textbf{Conclusion:}

This study of the first 20 patients prescribed selexipag in our centre
demonstrates that selexipag can be safely initiated, titrated and
transitioned in an outpatient setting to achieve an individualised
dosing regimen. Prostacyclin side effects were common, but improved in
the maintenance phase. There were no drug discontinuations or deaths in
this study, but close observation and consideration of clinical,
biochemical and hemodynamic parameters are recommended following any
changes in drug therapy.

\textbf{References} :

1. Lang IM and Gaine SP. Recent advances in targeting the prostacyclin
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2. Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for
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4. Menyhart K and Nayler O. Influence of IP Receptor Density on Agonist
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5. Farber HW and Gin-Sing W. Practical considerations for therapies
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6. Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of
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7. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral,
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8. Gomberg-Maitland M and Olschewski H. Prostacyclin therapies for the
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9. Surveillance for respiratory hazards in the occupational setting
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10. Kingman M, Archer-Chicko C, Bartlett M, et al. Management of
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11. Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan
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12. Sitbon O and Gaine S. Beyond a single pathway: combination therapy
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13. Sofer A, Ryan MJ, Tedford RJ, et al. A systematic review of
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10.1177/2045893217706357.

14. Chakinala MM, Feldman JP, Rischard F, et al. Transition from
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\emph{J Heart Lung Transplant} 2017; 36: 193-201. 2016/07/30. DOI:
10.1016/j.healun.2016.06.019.

15. Frost A, Janmohamed M, Fritz JS, et al. Safety and tolerability of
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16. Yanaka K, Guillien A, Soumagne T, et al. Transition from intravenous
epoprostenol to selexipag in pulmonary arterial hypertension: a word of
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18. Bhura S and Gibbons W. TRANSITIONING FROM INHALED ILOPROST TO ORAL
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19. Olschewski H, Simonneau G, Galiè N, et al. Inhaled Iloprost for
Severe Pulmonary Hypertension. \emph{New England Journal of Medicine}
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20. Nakayama K, Emoto N, Tamada N, et al. The optimization of iloprost
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22. Holthaus N, Prins K, Rose L, et al. EXPRESS: Transition from
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10.1124/jpet.116.239665.

\textbf{Tables:}

\textbf{Tables 1:}

Table 1 describes the baseline characteristics of patients, prior to the
initiation selexipag.

*Note data regarding 6MWD (N=16).\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Characteristics & N=20 (\%)\tabularnewline
\midrule
\endhead
Gender- Male / Female: no. (\%) & 7(35) / 13(65)\tabularnewline
Age: Mean (years) \selectlanguage{ngerman}± SD & 55 \selectlanguage{ngerman}± 17\tabularnewline
Time since PAH diagnosis - yr & 4 \selectlanguage{ngerman}± 4\tabularnewline
PAH classification &\tabularnewline
IPAH & 12 (60)\tabularnewline
CTD-PAH & 6 (30)\tabularnewline
Group 5 PH (Sarcoid) & 1 (5)\tabularnewline
Mixed disease & 1 (5)\tabularnewline
WHO functional class -- no. (\%) &\tabularnewline
I & 0\tabularnewline
II & 10 (50)\tabularnewline
III & 10 (50)\tabularnewline
IV & 0\tabularnewline
6-Minute walk distance* -- Mean (meters) \selectlanguage{ngerman}± SD & 331 \selectlanguage{ngerman}± 165\tabularnewline
Risk stratification &\tabularnewline
Low risk & 5 (25)\tabularnewline
Intermediate risk & 13 (65)\tabularnewline
High risk & 2 (10)\tabularnewline
Baseline medications for PAH -- no. (\%) &\tabularnewline
ERA+ PD5 inhibitors & 17 (85)\tabularnewline
ERA + sGC stimulator & 1 (5)\tabularnewline
ERA+ PD5 inhibitors + PGI2 therapy & 2 (10)\tabularnewline
Baseline medications (excluding targeted PAH med.) -- no. (\%)
&\tabularnewline
None & 1 (5)\tabularnewline
1-2 & 10 (50)\tabularnewline
3-6 & 7 (35)\tabularnewline
\emph{\textgreater{}}7 & 2 (10)\tabularnewline
Co-morbidities &\tabularnewline
None & 3 (15)\tabularnewline
Respiratory & 11 (55)\tabularnewline
Cardiovascular & 4 (20)\tabularnewline
Gastrointestinal & 4 (20)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2} :

Table 2 demonstrated the characteristics of selexipag titration and
maintenance doses at the end of the titration period and at 6 months
post selexipag initiation.\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Selexipag dosing &\tabularnewline
\midrule
\endhead
Titration period -- mean (days) \selectlanguage{ngerman}± SD & 67 \selectlanguage{ngerman}± 26\tabularnewline
Maintenance dose post titration -- mean daily dose (\selectlanguage{greek}μ\selectlanguage{english}g) \selectlanguage{ngerman}± SD & 1830 \selectlanguage{ngerman}±
548\tabularnewline
Subsequent dose changes at 6 months -- no. (\%) &\tabularnewline
No change & 15 (75)\tabularnewline
Dose increase & 2 (10)\tabularnewline
Dose reduction & 2 (10)\tabularnewline
Data missing & 1 (5)\tabularnewline
Drug discontinuation & 0\tabularnewline
Maintenance dose at 6 months -- mean daily dose (\selectlanguage{greek}μ\selectlanguage{english}g) \selectlanguage{ngerman}± SD & 1758 \selectlanguage{ngerman}±
620\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textbf{Table 3} :

Table 3 describes the maintenance dose ranges obtained at the end of the
initial titration period, which are classified as low (200-400 \selectlanguage{greek}μ\selectlanguage{english}g twice
daily) medium (600-- 1,000 \selectlanguage{greek}μ\selectlanguage{english}g twice daily) and high (1,200--1,600 \selectlanguage{greek}μ\selectlanguage{english}g
twice daily). Low, nedium and high dose definitions are derived from the
GRIPHON Study protocol.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
Maintenance doses (n=20)\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
Twice-daily dose (\selectlanguage{greek}μ\selectlanguage{english}g)\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
Patients N (\%)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Low-dose stratum\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
200\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
400\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
2 (10)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Medium-dose stratum\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
600\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1 (5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
800\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
6 (30)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1000\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
7 (35)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
High-dose stratum\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1200\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
2 (10)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1400\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
2 (10)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1600\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 4:}

Side effects reported during selexipag titration. 3 patients classified
as ``other'' reported increased thirst (n=1), insomnia (n=1) and cold
intolerance (n=1).\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Side effects & N=20 (\%)\tabularnewline
\midrule
\endhead
Nausea, GERD, Vomiting & 13 (65)\tabularnewline
Diarrhoea & 13 (65)\tabularnewline
Headache & 13 (65)\tabularnewline
Jaw discomfort & 9 (45)\tabularnewline
Myalgia, arthralgia & 7 (35)\tabularnewline
Abdominal cramps & 3 (15)\tabularnewline
Weight loss & 2 (10)\tabularnewline
Flushing & 2 (10)\tabularnewline
Clinical worsening of PAH & 1 (5)\tabularnewline
Other & 3 (15)\tabularnewline
\bottomrule
\end{longtable}

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

