HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use OPSUMIT safely and effectively. See full prescribing information for OPSUMIT.
OPSUMIT® (macitentan) tablets, for oral use
Initial U.S. Approval: 2013
WARNING: EMBRYO-FETAL TOXICITY
See full prescribing information for complete boxed warning
Do not administer OPSUMIT to a pregnant female because it may cause fetal harm (4.1, 5.1, 8.1).
Females of reproductive potential: exclude pregnancy before start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after treatment by using acceptable methods of contraception (2.2, 8.6).
For all female patients, OPSUMIT is available only through a restricted program called the OPSUMIT Risk eva luation and Mitigation Strategy (REMS) (5.2).
INDICATIONS AND USAGE
OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). OPSUMIT also reduced hospitalization for PAH (1.1).
DOSAGE AND ADMINISTRATION
10 mg once daily. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended (2.1).
DOSAGE FORMS AND STRENGTHS
Tablet: 10 mg (3)
CONTRAINDICATIONS
Pregnancy (4.1)
WARNINGS AND PRECAUTIONS
Other ERAs cause hepatotoxicity and liver failure. Obtain baseline liver enzymes and monitor as clinically indicated (5.3).
Decreases in hemoglobin (5.4).
Pulmonary edema in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment (5.5).
Decreases in sperm count have been observed in patients taking ERAs (5.6).
ADVERSE REACTIONS
Most common adverse reactions (more frequent than placebo by ≥3%) are anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and urinary tract infection (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Actelion at 1-866-228-3546 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Strong CYP3A4 inducers (rifampin) reduce exposure to macitentan: avoid co-administration with OPSUMIT (7.1, 12.3).
Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase exposure to macitentan: avoid co-administration with OPSUMIT (7.2, 12.3).
USE IN SPECIFIC POPULATIONS
Nursing mothers: discontinue OPSUMIT or breastfeeding (8.3).
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 10/2013
Actelion公司10月18日宣布，FDA已批准Opsumit（macitentan，10mg），作为每日一次的疗法，用于治疗肺动脉高压（PAH），以延缓疾病进展。该药是Actelion公司PAH药物Tracleer的继任者，Tracleer将于2015年失去专利保护。
Opsumit的获批，是基于在临床试验中可有效延缓疾病的进展。
Opsumit属于一类名为内皮素受体拮抗剂的药物，能够放松肺动脉并降低血压，Opsumit与该类药物中的其他药物一样，具有一个黑框警示，指出该药不可用于孕妇，因为Opsumit可能对胎儿造成伤害。
肺动脉高压（PAH）是一种极度严重的疾病，症状包括：呼吸短促、易于疲劳、晕厥、胸痛以及腿部和踝部水肿。此外，患者的肺动脉高压会逐步加重，甚至使寿命缩短。多数肺动脉高压相关的症状源自右心衰竭。
根据Actelion提供的数据，Tracleer在2012年的销售达15亿瑞士法郎，为该公司最畅销的药物。Actelion正指望Opsumit来弥补Tracleer专利到期所致的销售预期下降。
Opsumit将与市面上的其他PAH药物展开竞争，包括吉利德（Gilead）的Letairis，该药在美国以外国家和地区由葛兰素史克（GSK）以品牌名Volibris销售。
Back to Highlights and Tabs
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: EMBRYO-FETAL TOXICITY
1 INDICATIONS AND USAGE
1.1 Pulmonary Arterial Hypertension
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
2.2 Pregnancy Testing in Females of Reproductive Potential
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
4.1 Pregnancy
5 WARNINGS AND PRECAUTIONS
5.1 Embryo-fetal Toxicity
5.2 OPSUMIT REMS Program
5.3 Hepatotoxicity
5.4 Hemoglobin Decrease
5.5 Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)
5.6 Decreased Sperm Counts
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
7 DRUG INTERACTIONS
7.1 Strong CYP3A4 Inducers
7.2 Strong CYP3A4 Inhibitors
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric use
8.5 Geriatric use
8.6 Females and Males of Reproductive Potential
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology
14 CLINICAL STUDIES
14.1 Pulmonary Arterial Hypertension
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
WARNING: EMBRYO-FETAL TOXICITY
1 INDICATIONS AND USAGE
1.1 Pulmonary Arterial Hypertension
OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). OPSUMIT also reduced 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 were treated with OPSUMIT monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. 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%) [see Clinical Studies (14.1)].
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended dosage of OPSUMIT is 10 mg once daily for oral administration. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.
2.2 Pregnancy Testing in Females of Reproductive Potential
Initiate treatment with OPSUMIT in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy test during treatment [see Use in Specific Populations (8.6)].
3 DOSAGE FORMS AND STRENGTHS
Tablets: 10 mg, bi-convex film-coated, round, white, and debossed with "10" on one side.
4 CONTRAINDICATIONS
4.1 Pregnancy
OPSUMIT may cause fetal harm when administered to a pregnant woman. OPSUMIT is contraindicated in females who are pregnant. OPSUMIT was consistently shown to have teratogenic effects when administered to animals. If OPSUMIT is used during pregnancy, apprise the patient of the potential hazard to a fetus [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Embryo-fetal Toxicity
OPSUMIT may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods and obtain monthly pregnancy tests [see Dosage and Administration (2.2) and Use in Specific Populations (8.1, 8.6)].
OPSUMIT is available for females through the OPSUMIT REMS Program, a restricted distribution program [see Warnings and Precautions (5.2)].
5.2 OPSUMIT REMS Program
For all females, OPSUMIT is available only through a restricted program called the OPSUMIT REMS Program, because of the risk of embryo-fetal toxicity [see Contraindications (4.1), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)].
Notable requirements of the OPSUMIT REMS Program include the following:
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Prescribers must be certified with the program by enrolling and completing training.
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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.
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Females of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)].
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Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive OPSUMIT.
Further information is available at www.OPSUMITREMS.com or 1-866-228-3546. Information on OPSUMIT certified pharmacies or wholesale distributors is available through Actelion Pathways at 1-866-228-3546.
5.3 Hepatotoxicity
Other ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the study of OPSUMIT in PAH is shown in Table 1.
Table 1 Incidence of Elevated Aminotransferases in the SERAPHIN Study
|
|
OPSUMIT 10 mg
(N=242) |
Placebo
(N=249) |
|
>3 × ULN |
3.4% |
4.5% |
|
>8 × ULN |
2.1% |
0.4% |
In the placebo-controlled study of OPSUMIT, discontinuations for hepatic adverse events were 3.3% in the OPSUMIT 10 mg group 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 × 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.
5.4 Hemoglobin Decrease
Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with OPSUMIT. These decreases occurred early and stabilized thereafter. In the placebo-controlled study of OPSUMIT in PAH, OPSUMIT 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT 10 mg group and in 3.4% of the placebo group. 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 [see Adverse Reactions (6.1)].
