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OPSUMIT® (macitentan)

Medical Information

OPSUMIT - Reports of Hemoglobin Decrease and Anemia

Last Updated: 09/11/2025

SUMMARY

  • Decrease in hemoglobin (Hgb) concentration and hematocrit have occurred following administration of other endothelin receptor antagonists (ERA) and were observed in clinical studies with OPSUMIT.1
  • In a database consisting of pooled safety data collected from 3 placebo-controlled studies in different patient populations with various macitentan doses, decreased Hgb levels as an adverse event (AE) and anemia have been reported.2
  • In a phase 3 trial with a safety population of 742 patients with pulmonary arterial hypertension (PAH; randomized 1:1:1), a higher percentage of OPSUMIT and macitentan 3 mg treated patients experienced anemia vs patients receiving placebo (13.2%, 8.8%, and 3.2%, respectively). Three patients, 1 in each group, discontinued due to anemia.1
  • In the open-label (OL) extension study of SERAPHIN, 97 (17.6%) patients experienced anemia in the OL safety set with an incidence rate of 5.4 per 100 patient-years (PY) and 47 (19.4%) patients experienced anemia in the long-term safety/survival set with an incidence rate of 4.7 per 100 PYs. A total of 33 (6%) patients experienced Hgb levels ≤8 g/dL in the OL safety set with an incidence rate of 1.7 per 100 PYs and 15 (6.2%) patients experienced Hgb levels ≤8 g/dL in the long-term safety/survival set with an incidence rate of 1.4 per 100 PYs.3
  • Anemia/Hgb decrease-related AEs with OPSUMIT were reported in several other randomized clinical trials (RCT), including DUAL-1 and 2,4 MUSIC,5 MERIT-1 and 2,6,7 MAESTRO,8 RUBATO,9  and SERENADE.10  Results are summarized in the table below.
  • In the OPsumit USers Registry (OPUS) PAH follow-up set (N=2264), there were 175 (7.7%) patients who experienced anemia as an AE, and 234 (10.3%) patients who experienced anemia/Hgb decrease as an AE of special interest.11,12

CLINICAL DATA

Information From Macitentan Pooled Safety Data

A search of pooled safety data collected from 3 placebo-controlled studies with macitentan (PAH [SERAPHIN; macitentan 3 mg and 10 mg], essential hypertension [AC-055-201; macitentan 0.3 mg, 1 mg, 3 mg, and 10 mg], and idiopathic pulmonary fibrosis [IPF; MUSIC; OPSUMIT]) revealed that decreased Hgb levels and related AEs have been observed.2 In this pooled safety set, decreased Hgb levels were reported in 7 patients (0.8%) on macitentan and in 1 patient (0.3%) on placebo. Anemia was reported in 71 patients (8.2%) on macitentan and in 9 patients (2.4%) on placebo. Additional information on AEs related to decreased Hgb levels or anemia are summarized in Table: Incidence of AEs Related to Decreased Hgb Levels or Anemia in a Pooled Double-Blind Safety Set Comprising of AEs Reported During 3 Double-Blind Placebo-Controlled Studies With Macitentan and the proportion of patients and the extent of decreases in Hgb levels are provided in Table: Proportion of Patients With Hgb Levels Decreased to <10 g/dL, ≥8 g/dL to <10 g/dL, and <8 g/dL up to 28 Days After Discontinuation of Treatment in a Pooled Double-Blind Safety Set Comprising of AEs Reported During 3 Double-Blind Placebo-Controlled Studies With Macitentan below.2


Incidence of AEs Related to Decreased Hgb Levels or Anemia in a Pooled Double-Blind Safety Set Comprising of AEs Reported During 3 Double-Blind Placebo-Controlled Studies With Macitentan2
Adverse Event, n (%)
Macitentan
<3 mg
(n=129)
Macitentan
3 mg
(n=311)
OPSUMIT
(n=423)
Macitentan Total
(n=863)
Placebo
(n=370)
Anemia
3 (2.3)
22 (7.1)
46 (10.9)
71 (8.2)
9 (2.4)
Hgb decreased
–
1 (0.3)
6 (1.4)
7 (0.8)
1 (0.3)
Hematocrit decreased
–
1 (0.3)
6 (1.4)
7 (0.8)
–
Iron deficiency anemia
–
5 (1.6)
2 (0.5)
7 (0.8)
2 (0.5)
Hemorrhagic anemia
–
–
–
4 (0.5)
–
Hemolytic anemia
–
–
1 (0.2)
1 (0.1)
–
Autoimmune hemolytic anemia
–
–
–
–
1 (0.3)
Hypochromic anemia
–
–
–
1 (0.1)
–
Macrolytic anemia
–
–
–
–
1 (0.3)
Megaloblastic anemia
–
–
–
–
1 (0.3)
Abbreviations: Hgb, hemoglobin; n, number of patients with Hgb decrease; N, total number of patients included.

Proportion of Patients With Hgb Levels Decreased to <10 g/dL, ≥8 g/dL to <10 g/dL, and <8 g/dL up to 28 Days After Discontinuation of Treatment in a Pooled Double-Blind Safety Set Comprising of AEs Reported During 3 Double-Blind Placebo-Controlled Studies With Macitentan2
Hgb Decrease, n (%)
Macitentan
<3 mg
(n=125)
Macitentan
3 mg
(n=301)
OPSUMIT
(n=408)
Macitentan Total
(n=834)
Placebo
(n=353)
Hgb <10 g/dL
0
14 (4.7)
23 (5.6)
37 (4.4)
8 (2.3)
Hgb ≥8 g/dL and <10 g/dL
0
10 (3.3)
14 (3.4)
24 (2.9)
8 (2.3)
Hgb <8 g/dL
0
4 (1.3)
9 (2.2)
13 (1.6)
0
Abbreviations: Hgb, hemoglobin; n, number of patients with Hgb decrease; N, total number of patients included.

Information From the SERAPHIN Study in Patients With PAH

The Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome (SERAPHIN) trial was a multicenter, double-blind, randomized, placebo-controlled, event driven phase 3 study to assess the long-term safety and efficacy of OPSUMIT in patients with symptomatic PAH.1 Select exclusion criteria included patients with Hgb <75% of the lower limit of the normal range.13 Overall, 742 patients ≥12 years of age were randomized 1:1:1 to receive placebo (n=250), macitentan 3 mg (n=250), or OPSUMIT (n=242).1

One patient randomly assigned to placebo did not receive study drug, and was excluded from the safety analysis.1 At baseline, mean Hgb levels were 15.6 g/dL in the placebo group, 15.5 g/dL in the macitentan 3 mg group, and 15.6 g/dL in the OPSUMIT group.2 The mean change in Hgb levels from baseline to end of treatment (EOT) + 28 days for macitentan-treated patients versus placebo were -1.0 g/dL and -0.6 g/dL for OPSUMIT and macitentan 3 mg, respectively.14 Three patients, 1 in each group, discontinued due to anemia.1 The dose-dependent decrease in Hgb concentration was established early and stabilized after 4 to 12 weeks of treatment, with no further changes during chronic treatment.15 After discontinuation of the drug, the effect was reversible. Please refer to Table: SERAPHIN Hematologic Safety for a summary of the hematologic safety data in SERAPHIN.14


SERAPHIN Hematologic Safety14
Placebo
(n=249)
Macitentan 3 mg (n=250)
OPSUMIT
(n=242)
Median treatment duration, weeks
85.3
99.5
103.9
Adverse event, n (%)
    Anemiaa
8 (3.2)
22 (8.8)
32 (13.2)
    Iron deficiency anemia
2 (0.8)
5 (2)
2 (0.8)
    Hgb decreased
1 (0.4)
1 (0.4)
5 (2.1)
    Hematocrit decreased
–
1 (0.4)
3 (1.2)
    Hemolytic anemia
–
–
1 (0.4)
    Autoimmune hemolytic anemia
1 (0.4)
–
–
    Megaloblastic anemia
1 (0.4)
–
–
Laboratory abnormalities - no. (%)
    Hgb ≤8 g/dL
1/237 (0.4)
4/241 (1.7)
10/230 (4.3)
    Hgb >8 g/dL and ≤10 g/dL
7/237 (3)
11/241 (4.6)
10/230 (4.3)
    Hgb ≤10 g/dL
8/237 (3.4)
15/241 (6.2)
20/230 (8.7)
Abbreviations: Hgb, hemoglobin; AE, adverse event. aAEs shown occurred in more than 10% of patients in any treatment group during the treatment period and up to 28 days after treatment discontinuation.

In patients who experienced Hgb concentrations <10 g/dL, the decreases were associated with a medical history of anemia or were reported in the setting of concurrent clinical events including bleeding, iron or vitamin deficiency, whereas in some patients decreased Hgb was detected when the patient experienced cardiac failure and edema and/or renal failure.15 Other risk factors in the patient population included the use of concomitant anticoagulants, platelet inhibitors, and in some patients (with rheumatoid autoimmune diseases such as connective tissue disease [CTD]) corticosteroids or immunosuppressants.

Cases of anemia requiring blood transfusion have been reported with macitentan as with other ERAs.15 In the majority of patients who experienced Hgb concentration ≤8 g/dL or who required a transfusion, these events occurred in the context of hemorrhage (in particular gynecological and gastrointestinal bleeding), a medical history of anemia, or other confounding factors such as chronic renal failure.2 There were 30 patients (16 OPSUMIT, 9 macitentan 3 mg, and 5 placebo) with reports of severe anemia and/or need for transfusion.14 In total, 12 patients on OPSUMIT, 6 patients on macitentan 3 mg, and 4 patients on placebo required transfusion.2 Of the 12 patients on OPSUMIT requiring transfusion, 8 (67%) had recovered from Hgb decrease (defined as Hgb back to >10 g/dL or investigation indicated resolution). Of the patients in the macitentan 3 mg and placebo treatment groups requiring transfusion, 5 (83%) and 3 (75%) patients in their respective groups recovered from Hgb decrease.

In the OL extension study of SERAPHIN, 550 and 242 patients treated with OPSUMIT were included in the OL safety set and the long-term safety/survival set, respectively. The OL safety set consisted of patients who were previously randomized in SERAPHIN and received either OPSUMIT (n=182), macitentan 3 mg (n=185), or placebo (n=183). The long-term safety/survival set consisted of patients who were previously randomized to receive OPSUMIT in SERAPHIN (n=242).3

The median (min-max) exposure to OPSUMIT was 40.1 (0.1-130.5) months in the OL safety set and 54.7 (0.1-141.3) months in the long-term safety/survival set. A total of 97 (17.6%) patients experienced anemia in the OL safety set with an incidence rate of 5.4 per 100 PYs and 47 (19.4%) patients experienced anemia in the long-term safety/survival set with an incidence rate of 4.7 per 100 PYs. A total of 33 patients (6%) experienced Hgb levels ≤8 g/dL in the OL safety set with an incidence rate of 1.7 per 100 PYs and 15 patients (6.2%) experienced Hgb levels ≤8 g/dL in the long-term safety/survival set with an incidence rate of 1.4 per 100 PYs.3

Additional RCTs reporting anemia/Hgb decrease-related AEs with OPSUMIT are summarized  in Table: Information From Additional RCTs of OPSUMIT.


Information From Additional RCTs of OPSUMIT
Study Name
Study Design
Study Treatment Arms
Incidence of AEs Related to Anemia
Incidence of AEs Related to Decreased Hgb Levels
DUAL-1 and DUAL-24
Phase 3, prospective, randomized, placebo-controlled, DB, multicenter, parallel group studies that assessed the efficacy, safety and tolerability of macitentan in patients with ischemic DU associated with SSc
Patients were randomized 1:1:1 to receive OPSUMIT, macitentan 3 mg, or placebo once daily
DUAL-1 (N=289): OPSUMIT, n=97; macitentan 3 mg, n=95; placebo, n=97
DUAL-2: prematurely terminated with about 93% of planned enrollment (n=265 of 285 planned)
DUAL-1
OPSUMIT (n=97), n=8 (8.2%); macitentan 3 mg (n=94), n=5 (5.3%); placebo (n=97), n=7 (7.2%)
DUAL-2
OPSUMIT (n=87), n=11 (12.6%); macitentan 3 mg (n=88), n=6 (6.8%); placebo (n=89), n=5 (5.6%)
Hgb <10 g/dL and decrease from baseline of ≥1.6 g/dL:
DUAL-1
OPSUMIT, n/N=9/93 (9.7%); macitentan 3 mg, n/N=5/93 (5.4%); placebo, n/N=3/93 (3.2%)
DUAL-2
OPSUMIT, 11/86 (12.8%); macitentan 3 mg, 10/88 (11.4%); and placebo, 4/88 (4.5%)
MUSIC5
A prospective, randomized, DB, multicenter, parallel-group, placebo-controlled phase 2 proof of concept study in adult patients with IPF of <3 years duration and a histological pattern of UIP on surgical lung biopsy
Patients were randomized 2:1 to receive OPSUMIT or placebo once daily
N=178: OPSUMIT, n=119; placebo, n=59
OPSUMIT (average duration of exposure, 14.5 months), n=13 (10.9%); placebo (average duration of exposure, 15 months), n=0
MERIT-16    
MERIT-27 
A 24-week phase 2, DB, randomized, placebo-controlled study that assessed OPSUMIT in patients with inoperable CTEPH
Patients in WHO FC II-IV with a PVR ≥400 dyn·sec/cm5 and 6MWD 150-450m were randomized 1:1 to receive OPSUMIT or placebo once daily
A phase 2, multicenter, single-arm, OLE study that assessed the long-term safety and tolerability of OPSUMIT in patients with inoperable CTEPH.
Patients who completed 24 weeks of MERIT-1 entered MERIT-2 and received OPSUMIT once daily
N=80: OPSUMIT, n=40; placebo, n=40
Overall, 76 patients (OPSUMIT, n=40; placebo, n=36) from MERIT-1 entered MERIT-2 and were treated with OPSUMIT once daily
Observation starting from MERIT-2 enrollment, n (%):c
OPSUMIT (DB), 2 (5); placebo (DB), 8 (22.2)
Observation from MERIT-1 enrollment, n (%):c
OPSUMIT (long-term DB/OLE), 3 (7.5)
Decrease in Hgb, n (%)a
OPSUMIT, 6 (15); placebo, 0
Hb ≤8 g/dL, n (%)b
OPSUMIT, 0; placebo, 1 (3)
Hb decrease from baseline ≥2 g/dL, n (%)b
OPSUMIT, 11 (28); placebo, 8 (20)
Anemia/Hgb decreased
Observation starting from MERIT-2 enrollment, n (%):
OPSUMIT (DB), 8 (20); placebo (DB), 14 (38.9)
Incidence rate – per 100 PYs (95% CI):
OPSUMIT (DB), 6.3 (3.2-12.7); placebo (DB), 13.1 (7.8-22.1)
Observation starting from MERIT-1 enrollment, n (%):
OPSUMIT (long-term DB/OLE), 12 (30)
Incidence rate – per 100 PYs (95% CI):
OPSUMIT (long-term DB/OLE), 9.2 (5.3-16.3)
MAESTRO8
A 16-week, multicenter, DB, randomized, placebo-controlled, phase 3 study that evaluated the efficacy and safety of OPSUMIT in patients with ES
Patients aged ≥12 years and in WHO FC II-III were randomized 1:1 to receive placebo or OPSUMIT once daily
OPSUMIT, n=114; placebo, n=112
OPSUMIT, n=6 (5.3%); placebo, n=1 (0.9%)e
Change in Hgb levels from baseline to week 16/EOT, mean±SD, g/dL:
OPSUMIT, ‒1.04±1.37f; placebo, 0.12±1.22
Hgb decrease from baseline ≥2 g/dL, n (%):
OPSUMIT, 41 (36); placebo, 10 (8.9)
RUBATO (DB and OLE)9
A 52-week, prospective, multicenter, DB, randomized, placebo-controlled, parallel-group study that assessed the efficacy and safety of OPSUMIT in Fontan-palliated adult and adolescent patients
Patients aged ≥12 years who had undergone a TCPC (LT-TCPC or EC-TCPC) Fontan procedure >1 year before screening and were NYHA FC II or III were randomized 1:1 to receive OPSUMIT or placebo
Patients who completed 52 weeks of the DB treatment were eligible to enter the RUBATO-OLE study
RUBATO DB
N=137: OPSUMIT, n=68; placebo, n=69
Overall, 111 patients (OPSUMIT, n=57; placebo, n=54) from RUBATO DB entered RUBATO OLE and were treated with OPSUMIT once daily
Anemia and decreased Hgb AESIs in patients with ≥1 dose of OPSUMIT across RUBATO DB and OLE (n=122):
A mild AE was reported in 1 (0.8%) patient. TRAEs occurred in 1 (0.8%) patient.
SERENADE10 
An international, multicenter, randomized, DB, placebo-controlled, parallel-group, phase 2b study that evaluated the effects of OPSUMIT in patients with HF, LVEF ≥40%, and PVD
Patients who did not develop early OPSUMIT-induced fluid retention were randomized 1:1 to receive OPSUMIT or placebo once daily
N=142: OPSUMIT, n=71; placebo, n=71
OPSUMIT, n=21 (29.6%); placebo, n=9 (12.7%)
Hgb <10 g/dL, n (%)
OPSUMIT, 17 (23.9); placebo, 7 (9.9)
Hgb <8 g/dL, n (%)
OPSUMIT, 3 (4.2); placebo, 1 (1.4)
Abbreviations: 6MWD, 6-minute walk distance; AE, adverse event; AESI, adverse event of special interest; CTEPH, chronic thromboembolic pulmonary hypertension; DB, double-blind; DU, digital ulcers; EC-TCPC, extracardiac conduit total cavopulmonary connection; FC, functional class; Hgb, hemoglobin; IPF, idiopathic pulmonary fibrosis; LT-TCPC, lateral tunnel total cavopulmonary connection; MUSIC, Macitentan USe in an Idiopathic pulmonary fibrosis Clinical trial; NYHA, New York Heart Association; OLE, open-label extension; PVR, pulmonary vascular resistance; SSc, systemic sclerosis; TCPC, total cavopulmonary connection; UIP, interstitial pneumonia; WHO, World Health Organization. aAEs are listed for those that occurred in ≥3 patients in the OPSUMIT group. bHgb levels were measured at a central laboratory. cAEs ≥ 10% of patients in any group, by Preferred Term. dDuring the OLE period, reported as serious in 1 DB-OPSUMIT patient (day of AE onset: 1358); AESIs leading to premature studydrug discontinuation listed in 2 patients (1 DB-OPSUMIT and 1 DB-placebo; day of AE onset: 1083 and 37, respectively). eAESI related to anemia, edema and fluid overload, and hypotension were predefined in the analysis plan. fData were missing for 1 patient in the OPSUMIT group and 3 patients in the placebo group (a total of 4 patients with missing data).

Information From OPUS/OrPHeUS Registry

OPUS was a prospective, multicenter, long-term, observational drug registry in the United States (US) that enrolled patients from April 2014 and June 2020. New-user cohort design included patients newly treated with OPSUMIT, regardless of diagnosis and prior or ongoing PAH therapy. OPsumit Historical USers cohort study (OrPHeUS) was a retrospective, multicenter, US medical chart review that included patients who newly initiated OPSUMIT between October 2013 and December 2016 (inclusive), with individual patient data recorded up to March 2017. However, patients enrolled in OPUS were not allowed to participate in OrPHeUS.11

The median (quartile [Q1-Q3]) length of OPSUMIT exposure in the combined OPUS/OrPHeUS PAH follow-up set was 14.5 (5.2-29) months. In the OPUS PAH follow-up set (N=2264), there were 175 patients (7.7%) who experienced anemia as an AE, and 234 patients (10.3%) who experienced anemia/Hgb decrease as an AE of special interest.12 No data regarding anemia or Hgb decrease was reported in the combined OPUS/OrPHeUS set.

Literature Search

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) was conducted on 03 September 2025.

 

References

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1 Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-818.  
2 Data on File. Macitentan. Clinical Study Report, Hematology Safety Expert Report, PBRER - Reports of Hemoglobin Decrease and Anemia. Janssen Scientific Affairs, LLC; 2021.  
3 Souza R, Delcroix M, Galié N, et al. Long-term safety, tolerability and survival in patients with pulmonary arterial hypertension treated with macitentan: results from the SERAPHIN open-label extension. Adv Ther. 2022;39(9):4374-4390.  
4 Khanna D, Denton CP, Merkel PA, et al. Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis: DUAL-1 and DUAL-2 randomized clinical trials. JAMA. 2016;315(18):1975-1988.  
5 Raghu G, Million-Rousseau R, Morganti A, et al. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J. 2013;42(6):1622-1632.  
6 Ghofrani HA, Simonneau G, D’Armini AM, et al. Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. Lancet Respir Med. 2024;12(4):e21-e30.  
7 Kim NH, D’Armini AM, Howard LS, et al. Long-term safety and efficacy of macitentan in inoperable chronic thromboembolic pulmonary hypertension: results from MERIT and its open-label extension. Pulm Ther. 2025;11(1):101-116.  
8 Gatzoulis M, Landzberg M, Beghetti M, et al. Evaluation of macitentan in patients with Eisenmenger syndrome. Circulation. 2019;139(1):51-63.  
9 Clift P, Berger F, Sondergaard L, et al. Efficacy and safety of macitentan in Fontan-palliated patients: 52-week randomized, placebo-controlled RUBATO phase 3 trial and open-label extension. J Thorac Cardiovasc Surg. 2024;169(2):385-394.e5.  
10 Shah SJ, Bonderman D, Borlaug BA, et al. Macitentan for heart failure with preserved or mildly reduced ejection fraction and pulmonary vascular disease: results of the SERENADE randomized clinical trial and open-label extension study. Circ Heart Fail. 2025;18(3):e011381.  
11 McLaughlin VV, Channick R, Kim NH, et al. Safety of macitentan for the treatment of pulmonary hypertension: real-world experience from the OPsumit® USers Registry (OPUS) and OPsumit® Historical USers cohort (OrPHeUS). Pulm Circ. 2022;12(4):e12150.  
12 McLaughlin VV, Channick R, Kim NH, et al. Supplement to: Safety of macitentan for the treatment of pulmonary hypertension: real-world experience from the OPsumit® USers Registry (OPUS) and OPsumit® Historical USers cohort (OrPHeUS). Pulm Circ. 2022;12(4):e12150.  
13 Actelion Ltd. Study of macitentan (ACT-064992) on morbidity and mortality in patients with symptomatic pulmonary arterial hypertension (SERAPHIN). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2017]. Available from: https://clinicaltrials.gov/show/NCT00660179 NLM identifier: NCT00660179.  
14 Food and Drug Administration (FDA). Opsumit (macitentan) NDA 204410. Medical Review(s). Food and Drug Administration (FDA); 2013. Accessed January 10, 2024.  
15 Dingemanse J, Sidharta PN, Maddrey WC, et al. Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Expert Opin Drug Saf. 2014;13(3):391-405.