For U.S. Healthcare Professionals
PAH associated with connective tissue disease (PAH-CTD)
PAH: A potential complication of CTD affecting up to approximately 1 in 10 patients1
PAH is a well-known complication in some patients with CTD2:
- PAH affects approximately 3% to 13% of patients with CTD and 5% to 12% of patients with systemic sclerosis (SSc)1,3
- Patients with PAH-SSc have a worse prognosis than most other PAH-associated disease populations4
Exploratory subgroup analysis: Reduction in risk of disease progression in patients with PAH-CTD
Overall, in SERAPHIN, OPSUMIT® (macitentan) reduced the risk of disease progression by 45% vs placebo (HR 0.55; 97.5% CI, 0.39-0.76; P<0.0001).5 In the SERAPHIN trial, 31% of the overall patient population had PAH-CTD.5
POST HOC ANALYSIS: Time to first disease progression event in patients with PAH-CTD6
Summary of primary endpoint events in patients with PAH-CTD6
| OPSUMIT® 10 mg (n=73), n (%) | Placebo (n=82), n (%) | |
|---|---|---|
| Patients with a primary endpoint event* | 20 (27.4) | 31 (37.8) |
| Component as first event | ||
| Worsening PAH | 16 (21.9) | 25 (30.5) |
| Death | 3 (4.1) | 5 (6.1) |
| Initiation of IV/SC prostanoids | 1 (1.4) | 1 (1.2) |
*No patients experienced an event of lung transplantation or atrial septostomy in the placebo or OPSUMIT® 10 mg treatment groups.
Notable differences in PAH-CTD subgroup baseline characteristics compared with SERAPHIN overall population6,7
- Larger percentage of female patients (92% vs 76.5%)
- Older average age (49.7 years vs 45.6 years)
- Larger percentage of patients with WHO FC II symptoms (58.5% vs 52.4%)
- Lower percentage of patients with WHO FC Ill symptoms (39.3% vs 45.6%)
- Shorter time from diagnosis (mean 2.0 years vs 2.7 years)
Adverse reactions in the PAH-CTD subgroup notably different from the overall population6†
| OPSUMIT® 10 mg n=73 | Placebo n=82 | |
|---|---|---|
| Upper respiratory tract infection | 23.3% | 13.4% |
| Urinary tract infection | 12.3% | 6.1% |
| Skin ulcer | 9.6% | 3.7% |
| Sinusitis | 6.8% | 1.2% |
| Lower respiratory tract infection | 5.5% | 1.2% |
| Nausea | 8.2% | 4.9% |
†Only adverse reactions occurring ≥3% on OPSUMIT® compared with placebo and with placebo-corrected difference of ≥3% in the PAH-CTD subgroup vs the overall population are shown here.
Tolerability in the PAH-CTD subgroup was generally consistent with the overall population; however, 8 (9.8%) patients receiving placebo and 8 (11.0%) patients receiving OPSUMIT® 10 mg in the PAH-CTD subgroup discontinued treatment due to adverse reactions, compared with approximately 11% for both the placebo and OPSUMIT® in the overall population6,7
Exploratory subgroup analysis: Reduction in the risk of PAH-related hospitalization
Results from the PAH-CTD predetermined subgroup on a key secondary endpoint in SERAPHIN were consistent with the overall treatment effect.5,6
Overall, in SERAPHIN, OPSUMIT® reduced the risk of PAH-related hospitalization by 50% vs placebo (HR 0.50; 97.5% CI, 0.34-0.75; P<0.0001).5
POST HOC ANALYSIS: Time to PAH-related
death or hospitalization in patients with PAH-CTD6
PAH-CTD Subgroup: Summary of death due to PAH and hospitalization due to PAH6
| OPSUMIT® 10 mg (n=73), n (%) | Placebo (n=82), n (%) | |
|---|---|---|
| Death due to PAH or hospitalization for PAH | 13 (17.8) | 22 (26.8) |
| Component as first event | ||
| Death due to PAH | 1 (1.4) | 1 (1.2) |
| Hospitalization for PAH | 12 (16.4) | 21 (25.6) |
The reduction in risk of PAH-related hospitalization in patients with
PAH-CTD was consistent with that in the overall study population5,6
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IMPORTANT SAFETY INFORMATION
BOXED WARNING: EMBRYO-FETAL TOXICITY
- Do not administer OPSUMIT® to a pregnant female because it may cause fetal harm.
- Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception.
- For all female patients, OPSUMIT® is available only through a restricted program called the OPSUMIT® Risk Evaluation and Mitigation Strategy (REMS).
INDICATION
OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH.
Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).
CONTRAINDICATIONS
Pregnancy: OPSUMIT® may cause fetal harm when administered to a pregnant woman. OPSUMIT® is contraindicated in females who are pregnant. If OPSUMIT® is used during pregnancy, advise the patient of the potential risk to a fetus.
Hypersensitivity: OPSUMIT® is contraindicated in patients with a history of a hypersensitivity reaction to macitentan or any component of the product.
WARNINGS AND PRECAUTIONS
Embryo-fetal Toxicity and OPSUMIT® REMS Program
Due to the risk of embryo-fetal toxicity, OPSUMIT® is available for females only through a restricted program called the OPSUMIT® REMS Program. For females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests.
Notable requirements of the OPSUMIT® REMS Program include:
- Prescribers must be certified with the program by enrolling and completing training.
- All females, regardless of reproductive potential, must enroll in the OPSUMIT® REMS Program prior to initiating OPSUMIT®. Male patients are not enrolled in the REMS.
- Females of reproductive potential must comply with the pregnancy testing and contraception requirements.
- Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive OPSUMIT®.
Hepatotoxicity
- ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the SERAPHIN study >3 x ULN was 3.4% for OPSUMIT® vs 4.5% for placebo, and >8 x ULN was 2.1% vs 0.4%, respectively. Discontinuations for hepatic adverse events were 3.3% for OPSUMIT® vs 1.6% for placebo.
- Obtain liver enzyme tests prior to initiation of OPSUMIT® and repeat during treatment as clinically indicated.
- Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching).
- If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSUMIT®. Consider re-initiation of OPSUMIT® when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.
Fluid Retention
- Peripheral edema and fluid retention are known consequences of PAH and ERAs. In the pivotal PAH study SERAPHIN, edema was reported in 21.9% of the OPSUMIT® group vs 20.5% for placebo.
- Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment. In a small study of pulmonary hypertension due to left ventricular dysfunction, more patients in the OPSUMIT® group developed significant fluid retention and had more hospitalizations due to worsening heart failure compared to placebo. Postmarketing cases of edema and fluid retention occurring within weeks of starting OPSUMIT®, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, have been reported.
- Monitor for signs of fluid retention after OPSUMIT® initiation. If clinically significant fluid retention develops, evaluate the patient to determine the cause and the possible need to discontinue OPSUMIT®.
Hemoglobin Decrease
- Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and in clinical studies with OPSUMIT®. These decreases occurred early and stabilized thereafter.
- In the SERAPHIN study, OPSUMIT® caused a mean decrease in hemoglobin (from baseline to 18 months) of about 1.0 g/dL vs no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT® group vs 3.4% for placebo. Decreases in hemoglobin seldom require transfusion.
- Initiation of OPSUMIT® is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated.
Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)
Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue OPSUMIT®.
Decreased Sperm Counts
OPSUMIT®, like other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility.
ADVERSE REACTIONS
Most common adverse reactions (more frequent than placebo by ≥3%) were anemia (13% vs 3%), nasopharyngitis/pharyngitis (20% vs 13%), bronchitis (12% vs 6%), headache (14% vs 9%), influenza (6% vs 2%), and urinary tract infection (9% vs 6%).
DRUG INTERACTIONS
- Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of OPSUMIT® with strong CYP3A4 inducers should be avoided.
- Strong inhibitors of CYP3A4 like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of OPSUMIT® with strong CYP3A4 inhibitors. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment.
- Moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole and amiodarone are predicted to increase macitentan exposure. Avoid concomitant use of OPSUMIT® with moderate dual inhibitors of CYP3A4 and CYP2C9.
- Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSUMIT® should also be avoided.
INDICATION
OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH.
Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).
Please see full Prescribing Information, including BOXED WARNING.
To report suspected adverse reactions, contact Janssen at 1-800-JANSSEN (1-800-526-7736), or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
IMPORTANT SAFETY INFORMATION
BOXED WARNING: EMBRYO-FETAL TOXICITY
- Do not administer OPSUMIT® to a pregnant female because it may cause fetal harm.
- Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception.
- For all female patients, OPSUMIT® is available only through a restricted program called the OPSUMIT® Risk Evaluation and Mitigation Strategy (REMS).
INDICATION
OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH.
Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).
