SUMMARY

• Decrease in hemoglobin concentration and hematocrit have occurred following administration of other endothelin receptor antagonists (ERAs) 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 hemoglobin 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 and 47 (19.4%) patients experienced anemia in the long-term safety/survival set with an incidence rate of 4.7 per 100 patient-years. A total of 33 (6.0%) patients experienced hemoglobin levels ≤8 g/dL in the OL safety set with an incidence rate of 1.7 per 100 patient-years and 15 (6.2%) patients experienced hemoglobin levels ≤8 g/dL in the long-term safety/survival set with an incidence rate of 1.4 per 100 patient-years.³
• 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/hemoglobin decrease as an AE of special interest.^4,5
• In DUAL-1 and DUAL-2, phase 3 trials in patients with digital ulcers (DUs) associated with systemic sclerosis (SSc), anemia was reported in patients across all treatment arms (OPSUMIT, macitentan 3 mg, and placebo).⁶
• In the MUSIC trial, a phase 2 trial in patients with idiopathic pulmonary fibrosis (IPF), a higher percentage of OPSUMIT treated patients experienced anemia vs patients receiving placebo (10.9% vs 0%, respectively).⁷ In the MERIT-1 trial, a phase 2 trial in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), a higher percentage of OPSUMIT treated patients experienced a decrease in hemoglobin vs patients receiving placebo (15% vs 0%, respectively).⁸ In the MAESTRO trial, a phase 3 trial in patients with Eisenmenger syndrome, a higher percentage of OPSUMIT treated patients experienced anemia and a decrease in hemoglobin (from baseline ≥2 g/dL) vs patients receiving placebo (5.3% vs 0.9%; 36.0% vs 8.9%, respectively).⁹
• In the postmarketing period, cases of decreased hemoglobin levels or anemia have been reported. In some of these cases, blood transfusion was reported, mostly alongside confounding factors such as underlying conditions, bleeding events, or the underlying disease itself. Because these AEs are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.²

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 IPF [MUSIC; OPSUMIT]) revealed that decreased hemoglobin (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 AEs Reported During Three 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 AEs Reported During Three Double-Blind Placebo-Controlled Studies With Macitentan below.²

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.¹⁰ 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) and the mean treatment duration was 85.3, 99.5, and 103.9 weeks, respectively.¹

One patient randomly assigned to placebo did not receive study drug, and was excluded from the safety analysis.¹ At baseline, mean hemoglobin 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 hemoglobin 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.¹¹ Three patients, 1 in each group, discontinued due to anemia.¹ The dose-dependent decrease in hemoglobin concentration was established early and stabilized after 4 to 12 weeks of treatment, with no further changes during chronic treatment.¹² 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.¹¹

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 hemoglobin was detected when the patient experienced cardiac failure and edema and/or renal failure.¹² 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.¹² 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.¹¹ 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 hemoglobin decrease (defined as hemoglobin 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 hemoglobin 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 patient-years and 47 (19.4%) patients experienced anemia in the long-term safety/survival set with an incidence rate of 4.7 per 100 patient-years. A total of 33 (6.0%) patients experienced hemoglobin levels ≤8 g/dL in the OL safety set with an incidence rate of 1.7 per 100 patient-years and 15 (6.2%) patients experienced hemoglobin levels ≤8 g/dL in the long-term safety/survival set with an incidence rate of 1.4 per 100 patient-years.³

Information From the DUAL-1 and DUAL-2 Studies in Systemic Sclerosis

DUAL-1 and DUAL-2 were phase 3, prospective, randomized, placebo-controlled, double-blind, multicenter, parallel group studies to assess the efficacy, safety and tolerability of macitentan in patients with ischemic DU associated with SSc.^6,13,14 Patients were randomized in a 1:1:1 ratio to OPSUMIT, macitentan 3 mg, or placebo once daily.

The DUAL-1 study included 289 patients randomized to macitentan 3 mg (n=95), OPSUMIT (n=97), and placebo (n=97). The DUAL-2 study was prematurely terminated with about 93% of planned enrollment (n=265 of 285 planned). The decision followed the recommendation of the independent data monitoring committee, which determined that additional data were unlikely to result in a positive primary outcome measure.

The incidence of Hgb decrease and anemia during the DUAL-1 and DUAL-2 studies up to EOT + 30 days is summarized in Table: Hemoglobin and Anemia Reported in DUAL-1 and DUAL-2 Studies up to EOT + 30 Days below.¹⁵

Information From the MUSIC Study in Idiopathic Pulmonary Fibrosis

The Macitentan USe in an Idiopathic pulmonary fibrosis Clinical trial (MUSIC) trial was a prospective, randomized, double-blind, multicenter, parallel-group, placebo controlled phase 2 proof of concept trial.⁷ This study included 178 patients diagnosed with IPF according to the ATS/ERS consensus conference criteria with SLB.¹⁶ Adult patients with IPF of <3 years duration and a histological pattern of usual interstitial pneumonia (UIP) on surgical lung biopsy were randomized 2:1 to receive OPSUMIT (n=119) or placebo (n=59) once daily.

The safety set comprised 178 patients who received at least 1 dose of study treatment.⁷ Exposure to study treatment was similar in each group, with an average duration of 14.5 months in the OPSUMIT group and 15.0 months in the placebo group.

In total, 13 (10.9%) OPSUMIT-treated patients and 0 (0%) of placebo recipients experienced anemia.⁷

Information From the MERIT-1 Study in Inoperable Chronic Thromboembolic Pulmonary Hypertension

MERIT-1 was a phase 2, double-blind, randomized, placebo-controlled trial to assess OPSUMIT in 80 patients with inoperable CTEPH. Patients identified as WHO FC II-IV with a PVR ≥400 dyn·sec/cm⁵ and 6MWD 150-450m were randomly assigned 1:1 to receive OPSUMIT once a day (n=40) or placebo (n=40).⁸

The incidence of decreased hemoglobin and other laboratory findings of interest related to hemoglobin are summarized below in Table: Hemoglobin Reported in MERIT-1.⁸

Information From the MAESTRO Study in Eisenmenger Syndrome

MAESTRO was a multicenter, double-blind, randomized, placebo-controlled, 16-week, phase 3 study to evaluate the efficacy and safety of OPSUMIT in patients with Eisenmenger syndrome. Patients with Eisenmenger syndrome aged ≥12 years and in WHO FC II-III were randomized 1:1 to placebo or OPSUMIT once daily for 16 weeks.⁹

The incidence of anemia and hemoglobin decrease are summarized below in Table: Hemoglobin and Anemia Reported in MAESTRO.⁹

Information From OPUS/OrPHeUS Registry

OPUS was a prospective, multicenter, long-term, observational drug registry in the 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.⁴

The median (quartile 1, 3 [Q1, Q3]) length of OPSUMIT exposure in the combined OPUS/OrPHeUS PAH follow-up set was 14.5 (5.2, 29.0) months. In the 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/hemoglobin decrease as an AE of special interest.⁵ No data regarding anemia or hemoglobin decrease was reported in the combined OPUS/OrPHeUS set.

Information From Janssen’s Postmarketing Safety Database

As of October 2013 to October 2016, an estimated 28,239 patients had been exposed to OPSUMIT. Cases (serious and non-serious including related) of anemia/Hgb decrease have been reported to Janssen. In some of these cases (one third of cases of severe anemia), red blood cell transfusion was reported, mostly alongside confounding factors such as underlying conditions, bleeding events such as gastrointestinal (GI) hemorrhages or the underlying disease itself (eg, CTD). In one third of the severe cases of anemia, OPSUMIT was discontinued.²

Mechanism of Decreased Hemoglobin in Some Patients Treated With Macitentan

The exact mechanism responsible for the observed hemoglobin decreases is not known. Hemoglobin decreases seen with OPSUMIT in SERAPHIN were also consistent with the mean changes observed in previous studies in patients treated with other ERAs.¹ From preclinical and clinical macitentan data, hemolysis or bone marrow toxicity are not likely to be the mechanism of hemoglobin decrease.¹²

Increased plasma volume due to vasodilatation and decreased vascular permeability is a potential mechanism that could explain the hematological observations. Endothelin-1 (ET-1) is a potent vasoconstrictor and as such has experimentally been shown to be associated with a decrease in plasma volume and an increase in hematocrit without a change in red blood cell mass. These observations could also be related to the ability of ET-1 to increase capillary permeability. It is expected that these effects would be reversed by an ERA, especially in situations of increased plasma ET concentrations (e.g., in PAH).¹²

The expansion is probably not ‘hemodilution’ as observed after infusion of intravenous fluids, since sodium and albumin concentrations did not decrease, but is very similar to the ‘pseudo-anemia’ that is physiologically observed during pregnancy. In this situation, the hemoglobin decrease was shown to result from an increase in red blood cell volume masked by a larger increase in plasma volume.¹²

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 11 September 2024.