Trial Outcomes & Findings for Clinical Study to Assess the Long-term Safety and Tolerability of ACT 064992 in Patients With Symptomatic Pulmonary Arterial Hypertension (NCT NCT00667823)

NCT ID: NCT00667823

Last Updated: 2025-03-30

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

550 participants

Primary outcome timeframe

Up to 28 days after study treatment discontinuation (Up to 12 years)

Results posted on

2025-03-30

Participant Flow

Participant flow reported below is up to study closure.

Participant milestones

Participant milestones
Measure	Macitentan 10 mg Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Overall Study STARTED	550
Overall Study COMPLETED	334
Overall Study NOT COMPLETED	216

Reasons for withdrawal

Reasons for withdrawal
Measure	Macitentan 10 mg Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Overall Study Lost to Follow-up	5
Overall Study Adverse Event	7
Overall Study Death	182
Overall Study Withdrawal by Subject	12
Overall Study Other	8
Overall Study Missing (completion page missing)	2

Baseline Characteristics

Clinical Study to Assess the Long-term Safety and Tolerability of ACT 064992 in Patients With Symptomatic Pulmonary Arterial Hypertension

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Macitentan 10 mg n=550 Participants Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Age, Continuous	47.7 years STANDARD_DEVIATION 15.67 • n=93 Participants
Sex: Female, Male Female	440 Participants n=93 Participants
Sex: Female, Male Male	110 Participants n=93 Participants
Race/Ethnicity, Customized Asian	165 Participants n=93 Participants
Race/Ethnicity, Customized Other	13 Participants n=93 Participants
Race/Ethnicity, Customized White	372 Participants n=93 Participants
Region of Enrollment ARGENTINA	32 Participants n=93 Participants
Region of Enrollment AUSTRALIA	6 Participants n=93 Participants
Region of Enrollment AUSTRIA	4 Participants n=93 Participants
Region of Enrollment BELARUS	21 Participants n=93 Participants
Region of Enrollment BELGIUM	2 Participants n=93 Participants
Region of Enrollment BULGARIA	4 Participants n=93 Participants
Region of Enrollment CANADA	12 Participants n=93 Participants
Region of Enrollment CHILE	24 Participants n=93 Participants
Region of Enrollment CHINA	74 Participants n=93 Participants
Region of Enrollment COLOMBIA	7 Participants n=93 Participants
Region of Enrollment FRANCE	8 Participants n=93 Participants
Region of Enrollment GERMANY	27 Participants n=93 Participants
Region of Enrollment HONG KONG	3 Participants n=93 Participants
Region of Enrollment HUNGARY	4 Participants n=93 Participants
Region of Enrollment INDIA	30 Participants n=93 Participants
Region of Enrollment ISRAEL	10 Participants n=93 Participants
Region of Enrollment ITALY	3 Participants n=93 Participants
Region of Enrollment MALAYSIA	6 Participants n=93 Participants
Region of Enrollment MEXICO	33 Participants n=93 Participants
Region of Enrollment NETHERLANDS	1 Participants n=93 Participants
Region of Enrollment PERU	4 Participants n=93 Participants
Region of Enrollment POLAND	19 Participants n=93 Participants
Region of Enrollment ROMANIA	12 Participants n=93 Participants
Region of Enrollment RUSSIAN FEDERATION	54 Participants n=93 Participants
Region of Enrollment SERBIA	13 Participants n=93 Participants
Region of Enrollment SINGAPORE	12 Participants n=93 Participants
Region of Enrollment SLOVAKIA	4 Participants n=93 Participants
Region of Enrollment SOUTH AFRICA	17 Participants n=93 Participants
Region of Enrollment SWEDEN	6 Participants n=93 Participants
Region of Enrollment TAIWAN	14 Participants n=93 Participants
Region of Enrollment THAILAND	19 Participants n=93 Participants
Region of Enrollment UKRAINE	12 Participants n=93 Participants
Region of Enrollment UNITED KINGDOM	4 Participants n=93 Participants
Region of Enrollment UNITED STATES	49 Participants n=93 Participants

PRIMARY outcome

Timeframe: Up to 28 days after study treatment discontinuation (Up to 12 years)

Population: The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).

Outcome measures

Outcome measures
Measure	Macitentan 10 mg n=550 Participants Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) up to 28 Days After Study Treatment Discontinuation	527 Participants

PRIMARY outcome

Timeframe: Up to 28 days after study treatment discontinuation (Up to 12 years)

Population: The SAF included all participants who received at least 1 dose of macitentan 10 mg.

Number of participants with deaths up to 28 days after study treatment discontinuation were reported.

Outcome measures

Outcome measures
Measure	Macitentan 10 mg n=550 Participants Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Number of Participants With Death up to 28 Days After Study Treatment Discontinuation	175 Participants

PRIMARY outcome

Timeframe: Up to 28 days after study treatment discontinuation (Up to 12 years)

Population: The SAF included all participants who received at least 1 dose of macitentan 10 mg.

An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically significant, or requires intervention to prevent at least one of the outcomes listed above.

Outcome measures

Outcome measures
Measure	Macitentan 10 mg n=550 Participants Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) up to 28 Days After Study Treatment Discontinuation	354 Participants

PRIMARY outcome

Timeframe: Up to 28 days after study treatment discontinuation (Up to12 years)

Population: The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 mg.

Number of participants with AEs leading to permanent discontinuation of study treatment were reported. An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

Outcome measures

Outcome measures
Measure	Macitentan 10 mg n=550 Participants Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment	62 Participants

PRIMARY outcome

Timeframe: Up to 28 days after study treatment discontinuation (Up to12 years)

Population: The SAF included all participants who received at least 1 dose of macitentan 10 mg.

Number of participants with treatment-emergent abnormal liver tests: Alanine aminotransferase (ALT) greater than (\>) 3\*upper limit of normal (ULN) or aspartate aminotransferase (AST) \>3\* ULN, ALT \>5\* ULN or AST \>5\*ULN, ALT \>8\*ULN or AST \>8\*ULN, total bilirubin (TBIL) \>2\*ULN, ALT \>3\*ULN or AST \>3\*ULN and TBIL \>2\*ULN at any time were reported.

Outcome measures

Outcome measures
Measure	Macitentan 10 mg n=550 Participants Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation ALT or AST >3*ULN	45 Participants
Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation ALT or AST >5*ULN	20 Participants
Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation ALT or AST >8*ULN	11 Participants
Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation TBIL >2*ULN	75 Participants
Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation ALT or AST >3ULN and (TBIL>2ULN at any time)	8 Participants

PRIMARY outcome

Timeframe: Up to 28 days after treatment discontinuation (Up to 12 years)

Population: The SAF included all participants who received at least 1 dose of macitentan 10 mg.

Number of participants with treatment-emergent hemoglobin (HGB) abnormality up to 28 days after study treatment discontinuation were reported. Participants assessed for different categories of HGB were \<=80 grams/Liter (g/L), \<=100g/L, decrease from baseline \>=20 g/L, and decrease from baseline \>=50 g/L.

Outcome measures

Outcome measures
Measure	Macitentan 10 mg n=550 Participants Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation HGB <= 80 gram/Liter (g/L)	33 Participants
Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation HGB <= 100 g/L	98 Participants
Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation HGB decrease from baseline >= 20 g/L	188 Participants
Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation HGB decrease from baseline >= 50 g/L	29 Participants

Adverse Events

Macitentan 10 mg

Serious events: 354 serious events

Other events: 476 other events

Deaths: 182 deaths

Serious adverse events

Serious adverse events
Measure	Macitentan 10 mg n=550 participants at risk Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Blood and lymphatic system disorders Anaemia	4.9% 27/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Blood and lymphatic system disorders Autoimmune Haemolytic Anaemia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Blood and lymphatic system disorders Coagulopathy	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Blood and lymphatic system disorders Hypercoagulation	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Blood and lymphatic system disorders Iron Deficiency Anaemia	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Blood and lymphatic system disorders Pancytopenia	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Acute Coronary Syndrome	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Acute Myocardial Infarction	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Acute Right Ventricular Failure	2.0% 11/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Angina Pectoris	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Arrhythmia	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Atrial Fibrillation	1.3% 7/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Atrial Flutter	1.5% 8/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Bradycardia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Cardiac Arrest	1.6% 9/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Cardiac Disorder	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Cardiac Failure	1.3% 7/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Cardiac Failure Acute	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Cardiac Failure Chronic	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Cardiac Failure Congestive	1.1% 6/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Cardio-Respiratory Arrest	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Cardiogenic Shock	1.6% 9/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Cardiopulmonary Failure	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Cardiorenal Syndrome	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Chronic Right Ventricular Failure	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Coronary Artery Disease	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Cyanosis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Left Ventricular Dysfunction	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Left Ventricular Failure	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Myocardial Infarction	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Myocardial Ischaemia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Palpitations	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Pericardial Effusion	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Right Ventricular Dysfunction	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Right Ventricular Failure	13.1% 72/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Stress Cardiomyopathy	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Supraventricular Tachycardia	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Tachyarrhythmia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Ventricular Fibrillation	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Ventricular Tachycardia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Ear and labyrinth disorders Vertigo Positional	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Eye disorders Cataract	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Abdominal Distension	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Abdominal Pain	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Abdominal Pain Upper	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Anal Fistula	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Ascites	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Colitis	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Diarrhoea	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Duodenal Perforation	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Enterocolitis Haemorrhagic	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Gastritis	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Gastritis Erosive	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Gastroduodenitis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Gastrointestinal Disorder	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Gastrointestinal Haemorrhage	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Gastrointestinal Necrosis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Haematemesis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Hiatus Hernia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Ileus Paralytic	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Intestinal Pseudo-Obstruction	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Lower Gastrointestinal Haemorrhage	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Pancreatitis Acute	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Pancreatitis Relapsing	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Peptic Ulcer	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Rectal Haemorrhage	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Small Intestinal Obstruction	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Umbilical Hernia	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Upper Gastrointestinal Haemorrhage	1.1% 6/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Vomiting	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Cardiac Death	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Chest Discomfort	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Chest Pain	2.0% 11/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Death	0.91% 5/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Drug Ineffective	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Fatigue	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders General Physical Health Deterioration	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Influenza Like Illness	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Infusion Site Pain	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Multiple Organ Dysfunction Syndrome	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Oedema Peripheral	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Peripheral Swelling	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Pyrexia	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Sudden Cardiac Death	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Sudden Death	2.0% 11/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Vascular Stent Thrombosis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Hepatobiliary disorders Bile Duct Stone	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Hepatobiliary disorders Cholecystitis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Hepatobiliary disorders Cholecystitis Acute	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Hepatobiliary disorders Cholelithiasis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Hepatobiliary disorders Hepatic Function Abnormal	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Hepatobiliary disorders Hepatic Steatosis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Immune system disorders Drug Hypersensitivity	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Abscess Limb	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Appendicitis	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Arthritis Bacterial	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Atypical Pneumonia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Bronchitis	1.6% 9/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Bronchitis Viral	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Candida Sepsis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Cellulitis	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Device Related Infection	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Endocarditis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Erysipelas	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Gastroenteritis	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Gastroenteritis Bacterial	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Gastroenteritis Norovirus	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Gastroenteritis Salmonella	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Herpes Zoster	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Hiv Infection	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Infected Skin Ulcer	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Infective Exacerbation of Chronic Obstructive Airways Disease	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Influenza	0.91% 5/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Joint Tuberculosis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Laryngitis Bacterial	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Localised Infection	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Lower Respiratory Tract Infection	1.5% 8/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Lung Infection	1.5% 8/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Meningitis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Peritonitis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Pneumococcal Sepsis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Pneumonia	7.3% 40/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Pneumonia Influenzal	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Pneumonia Klebsiella	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Pneumonia Streptococcal	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Postoperative Wound Infection	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Pulmonary Sepsis	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Pulmonary Tuberculosis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Pyelonephritis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Pyelonephritis Acute	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Respiratory Tract Infection	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Respiratory Tract Infection Viral	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Salmonella Sepsis	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Sepsis	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Septic Shock	1.1% 6/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Staphylococcal Bacteraemia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Subcutaneous Abscess	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Tuberculosis	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Upper Respiratory Tract Infection	1.5% 8/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Urinary Tract Infection	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Urosepsis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Viral Upper Respiratory Tract Infection	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Accidental Overdose	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Acetabulum Fracture	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Ankle Fracture	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Brain Contusion	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Contusion	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Fall	0.91% 5/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Femoral Neck Fracture	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Femur Fracture	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Foot Fracture	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Humerus Fracture	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Perineal Injury	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Post Procedural Haematoma	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Post Procedural Haemorrhage	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Radius Fracture	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Spinal Compression Fracture	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Subarachnoid Haemorrhage	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Subdural Haematoma	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Thermal Burn	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Thoracic Vertebral Fracture	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Toxicity to Various Agents	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Traumatic Haematoma	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Traumatic Haemorrhage	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Ulna Fracture	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Upper Limb Fracture	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Anticoagulation Drug Level above Therapeutic	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Blood Bilirubin Increased	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Catheterisation Cardiac	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Computerised Tomogram Abnormal	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations International Normalised Ratio Increased	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Investigation	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Liver Function Test Increased	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Oxygen Saturation Decreased	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Dehydration	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Electrolyte Imbalance	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Fluid Overload	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Fluid Retention	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Gout	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Hyperkalaemia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Hypoglycaemia	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Hypokalaemia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Hyponatraemia	0.91% 5/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Metabolic Acidosis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Back Pain	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Intervertebral Disc Degeneration	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Intervertebral Disc Protrusion	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Joint Swelling	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Mixed Connective Tissue Disease	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Muscular Weakness	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Osteoporosis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Pain in Extremity	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Polymyositis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Rheumatoid Arthritis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Scleroderma	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Spinal Column Stenosis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Systemic Lupus Erythematosus	0.91% 5/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Systemic Scleroderma	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Anogenital Warts	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal Cell Carcinoma	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder Cancer	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Brain Neoplasm	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cardiac Valve Fibroelastoma	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon Cancer	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Haemangioma	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Intraductal Proliferative Breast Lesion	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive Ductal Breast Carcinoma	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to Lung	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic Uterine Cancer	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Nasopharyngeal Cancer	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian Adenoma	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian Cancer	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectosigmoid Cancer Recurrent	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Richter's Syndrome	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous Cell Carcinoma of Lung	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous Cell Carcinoma of the Cervix	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine Cancer	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine Leiomyoma	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Amnesia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Brain Oedema	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Cerebellar Infarction	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Cerebrovascular Accident	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Dizziness	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Headache	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Hepatic Encephalopathy	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Ischaemic Stroke	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Loss of Consciousness	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Polyneuropathy	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Radiculopathy	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Syncope	3.6% 20/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Pregnancy, puerperium and perinatal conditions Abortion Missed	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Pregnancy, puerperium and perinatal conditions Abortion Spontaneous	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Pregnancy, puerperium and perinatal conditions Pregnancy	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Product Issues Device Dislocation	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Product Issues Device Malfunction	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Psychiatric disorders Anxiety	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Psychiatric disorders Anxiety Disorder	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Psychiatric disorders Completed Suicide	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Psychiatric disorders Confusional State	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Psychiatric disorders Depression	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Psychiatric disorders Mental Status Changes	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Acute Kidney Injury	1.5% 8/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Calculus Urinary	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Chronic Kidney Disease	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Cystitis Haemorrhagic	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Lupus Nephritis	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Nephrolithiasis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Neurogenic Bladder	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Pollakiuria	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Prerenal Failure	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Renal Colic	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Renal Failure	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Renal Impairment	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Ureterolithiasis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Reproductive system and breast disorders Dysmenorrhoea	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Reproductive system and breast disorders Menometrorrhagia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Reproductive system and breast disorders Menorrhagia	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Reproductive system and breast disorders Metrorrhagia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Reproductive system and breast disorders Ovarian Cyst	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Reproductive system and breast disorders Ovarian Cyst Ruptured	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Reproductive system and breast disorders Ovarian Cyst Torsion	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Reproductive system and breast disorders Pelvic Haematoma	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Reproductive system and breast disorders Prostatitis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Reproductive system and breast disorders Uterine Haemorrhage	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Reproductive system and breast disorders Vaginal Haemorrhage	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Acute Pulmonary Oedema	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Acute Respiratory Failure	0.73% 4/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Asthma	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Bronchitis Chronic	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Chronic Obstructive Pulmonary Disease	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Chronic Respiratory Failure	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.9% 16/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Dyspnoea Exertional	0.91% 5/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Epistaxis	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Haemoptysis	1.5% 8/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Hypoxia	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Nasal Polyps	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Organising Pneumonia	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Pleural Effusion	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Pulmonary Arterial Hypertension	22.4% 123/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Pulmonary Congestion	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Pulmonary Embolism	1.8% 10/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Pulmonary Fibrosis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Pulmonary Haemorrhage	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Pulmonary Hypertension	1.1% 6/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Pulmonary Hypertensive Crisis	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Pulmonary Oedema	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Respiratory Failure	0.91% 5/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Respiratory Tract Haemorrhage	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Skin and subcutaneous tissue disorders Photosensitivity Reaction	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Skin and subcutaneous tissue disorders Rash Pruritic	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Surgical and medical procedures Aortic Surgery	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Surgical and medical procedures Bunion Operation	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Surgical and medical procedures Chemotherapy	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Surgical and medical procedures Cholecystectomy	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Surgical and medical procedures Gastric Polypectomy	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Surgical and medical procedures Hysterectomy	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Surgical and medical procedures Lung Transplant	1.3% 7/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Surgical and medical procedures Oophorectomy	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Surgical and medical procedures Osteosynthesis	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Surgical and medical procedures Therapy Cessation	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Surgical and medical procedures Transfusion	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Accelerated Hypertension	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Aneurysm Ruptured	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Aortic Aneurysm	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Aortic Aneurysm Rupture	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Circulatory Collapse	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Deep Vein Thrombosis	0.36% 2/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Haematoma	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Hypertension	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Hypotension	0.55% 3/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Hypovolaemic Shock	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Venous Thrombosis Limb	0.18% 1/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).

Other adverse events

Other adverse events
Measure	Macitentan 10 mg n=550 participants at risk Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment.
Blood and lymphatic system disorders Anaemia	14.5% 80/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Blood and lymphatic system disorders Iron Deficiency Anaemia	2.5% 14/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Blood and lymphatic system disorders Leukopenia	4.0% 22/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Blood and lymphatic system disorders Thrombocytopenia	6.5% 36/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Atrial Fibrillation	4.4% 24/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Palpitations	6.2% 34/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Right Ventricular Failure	4.4% 24/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Cardiac disorders Tachycardia	4.0% 22/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Endocrine disorders Hypothyroidism	3.8% 21/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Abdominal Distension	2.5% 14/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Abdominal Pain	2.2% 12/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Abdominal Pain Upper	4.0% 22/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Constipation	3.6% 20/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Diarrhoea	10.7% 59/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Dyspepsia	2.4% 13/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Gastritis	2.0% 11/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Gastrooesophageal Reflux Disease	3.8% 21/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Nausea	5.1% 28/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Gastrointestinal disorders Vomiting	4.4% 24/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Chest Pain	6.4% 35/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Fatigue	3.5% 19/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Oedema Peripheral	19.1% 105/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
General disorders Pyrexia	4.5% 25/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Hepatobiliary disorders Hyperbilirubinaemia	4.7% 26/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Bronchitis	14.2% 78/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Cellulitis	2.0% 11/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Cystitis	2.0% 11/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Gastroenteritis	2.9% 16/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Influenza	3.1% 17/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Laryngitis	2.0% 11/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Lower Respiratory Tract Infection	2.2% 12/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Nasopharyngitis	19.1% 105/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Pharyngitis	5.1% 28/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Pneumonia	5.3% 29/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Respiratory Tract Infection	5.6% 31/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Respiratory Tract Infection Viral	4.2% 23/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Rhinitis	2.9% 16/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Sinusitis	3.3% 18/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Tooth Abscess	2.0% 11/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Upper Respiratory Tract Infection	22.0% 121/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Infections and infestations Urinary Tract Infection	8.4% 46/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Injury, poisoning and procedural complications Ligament Sprain	2.0% 11/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Alanine Aminotransferase Increased	4.0% 22/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Aspartate Aminotransferase Increased	3.6% 20/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Blood Bilirubin Increased	2.9% 16/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Blood Creatinine Increased	2.2% 12/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Haemoglobin Decreased	2.4% 13/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Liver Function Test Increased	2.7% 15/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Investigations Weight Decreased	3.5% 19/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Decreased Appetite	3.3% 18/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Gout	2.9% 16/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Hyperglycaemia	2.0% 11/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Hyperkalaemia	2.9% 16/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Hyperuricaemia	2.7% 15/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Metabolism and nutrition disorders Hypokalaemia	7.1% 39/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Arthralgia	6.0% 33/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Back Pain	6.0% 33/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Myalgia	2.7% 15/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Osteoarthritis	2.2% 12/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Musculoskeletal and connective tissue disorders Pain in Extremity	3.8% 21/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Dizziness	10.0% 55/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Headache	11.5% 63/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Nervous system disorders Syncope	7.3% 40/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Psychiatric disorders Anxiety	2.4% 13/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Psychiatric disorders Depression	2.2% 12/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Psychiatric disorders Insomnia	6.5% 36/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Renal and urinary disorders Acute Kidney Injury	2.5% 14/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Cough	13.5% 74/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Dyspnoea	9.8% 54/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Epistaxis	4.9% 27/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Haemoptysis	3.3% 18/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Nasal Congestion	2.5% 14/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Oropharyngeal Pain	3.3% 18/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Respiratory, thoracic and mediastinal disorders Pulmonary Arterial Hypertension	8.5% 47/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Skin and subcutaneous tissue disorders Rash	2.9% 16/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Skin and subcutaneous tissue disorders Skin Ulcer	2.4% 13/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
Vascular disorders Hypotension	3.6% 20/550 • Up to end of treatment plus 28 days for serious and other (non-serious) adverse events (Up to 11 years) and up to end of study for all-cause mortality (Up to 12 years) The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).

Additional Information

Senior Clinical Leader PH

Actelion Pharmaceuticals Ltd

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.
Publication restrictions are in place

Restriction type: OTHER