Opsumit 10 MG Oral Tablet
Generic Name: MACITENTAN
Brand Name: OPSUMIT
- Substance Name(s):
- MACITENTAN
DRUG INTERACTIONS
7 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 ) .
Moderate dual CYP3A4 and CYP2C9 inhibitors (fluconazole, amiodarone) or use of combined CYP3A4 and CYP2C9 inhibitors may increase exposure to macitentan: avoid co-administration with OPSUMIT ( 7.3 , 12.3 ).
7.1 Strong CYP3A4 Inducers Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure.
Concomitant use of OPSUMIT with strong CYP3A4 inducers should be avoided [see Clinical Pharmacology (12.3) ] .
7.2 Strong CYP3A4 Inhibitors Concomitant use of strong CYP3A4 inhibitors 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 [see Clinical Pharmacology (12.3) ] .
Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment [see Clinical Pharmacology (12.3) ] .
7.3 Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole is predicted to increase macitentan exposure approximately 4-fold based on physiologically based pharmacokinetic (PBPK) modelling.
Avoid concomitant use of OPSUMIT with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone) [see Clinical Pharmacology (12.3) ] .
Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSUMIT should also be avoided [see Clinical Pharmacology (12.3) ].
OVERDOSAGE
10 OPSUMIT has been administered as a single dose of up to and including 600 mg to healthy subjects (60 times the approved dosage).
Adverse reactions of headache, nausea and vomiting were observed.
In the event of an overdose, standard supportive measures should be taken, as required.
Dialysis is unlikely to be effective because macitentan is highly protein-bound.
DESCRIPTION
11 OPSUMIT ® (macitentan) is an endothelin receptor antagonist.
The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide.
It has a molecular formula of C 19 H 20 Br 2 N 6 O 4 S and a molecular weight of 588.27.
Macitentan is achiral and has the following structural formula: Macitentan is a crystalline powder that is insoluble in water.
In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive.
OPSUMIT is available as a 10 mg film-coated tablet for once daily oral administration.
The tablets include the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A.
The tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum.
Chemical Structure
CLINICAL STUDIES
14 14.1 Pulmonary Arterial Hypertension The effect of macitentan on progression of PAH was demonstrated in a multi-center, long-term (average duration of exposure approximately 2 years), placebo-controlled study in 742 patients with symptomatic [WHO functional class (FC) II–IV] PAH who were randomized to placebo (n=250), 3 mg macitentan (n=250), or 10 mg macitentan (n=242) once daily.
Patients were treated with OPSUMIT monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids.
The primary study endpoint was time to the first occurrence of death, a significant morbidity event, defined as atrial septostomy, lung transplantation, initiation of IV or subcutaneous (SC) prostanoids, or “other worsening of PAH” during double-blind treatment plus 7 days.
Other worsening was defined as all of the following: 1) a sustained ≥15% decrease from baseline in 6 minute walk distance (6MWD), 2) worsening of PAH symptoms (worsening of WHO FC), and 3) need for additional treatment for PAH.
All of these other worsening events were confirmed by an independent adjudication committee, blinded to treatment allocation.
A critical secondary endpoint was time to PAH death or PAH hospitalization.
The mean patient age was 46 years (14% were age 65 or above).
Most patients were white (55%) or Asian (29%) and female (77%).
Approximately 52%, 46%, and 2% of patients were in WHO FC II, III, and IV, respectively.
Idiopathic or heritable PAH was the most common etiology in the study population (57%) followed by PAH caused by connective tissue disorders (31%), PAH caused by congenital heart disease with repaired shunts (8%), and PAH caused by other etiologies [drugs and toxins (3%) and HIV (1%)].
At baseline, the majority of enrolled patients (64%) were being treated with a stable dose of specific therapy for PAH, either oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostanoids (6%).
Study results are described for the placebo and OPSUMIT 10 mg groups.
The median treatment durations were 101 and 118 weeks in the placebo and OPSUMIT 10 mg groups, respectively, up to a maximum of 188 weeks.
Treatment with OPSUMIT 10 mg resulted in a 45% reduction (HR 0.55, 97.5% CI 0.39–0.76; logrank p<0.0001) in the occurrence of the primary endpoint up to end of double-blind treatment compared to placebo (Table 3 and Figure 2).
The beneficial effect of OPSUMIT 10 mg was primarily attributable to a reduction in clinical worsening events (deterioration in 6MWD and worsening of PAH symptoms and need for additional PAH treatment).
Figure 2 Kaplan-Meier Estimates of the Occurrence of the Primary Endpoint Event in the SERAPHIN Study Table 3: Summary of Primary Endpoint Events Placebo N=250 n (%) OPSUMIT 10 mg N=242 n (%) Patients with a primary endpoint event No patients experienced an event of lung transplantation or atrial septostomy in the placebo or OPSUMIT 10 mg treatment groups.
116 (46.4) 76 (31.4) Component as first event Worsening PAH 93 (37.2) 59 (24.4) Death 17 (6.8) 16 (6.6) IV/SC prostanoid 6 (2.4) 1 (0.4) Subgroup analyses were performed to examine their influence on outcome as shown in Figure 3.
Consistent efficacy of OPSUMIT 10 mg on the primary endpoint was seen across subgroups of age, sex, race, etiology, by monotherapy or in combination with another PAH therapy, baseline 6MWD, and baseline WHO FC.
Figure 3 Subgroup Analysis of the SERAPHIN Study Eo = Number of events OPSUMIT 10 mg; No = Number of patients randomized to OPSUMIT 10 mg Ep = Number of events placebo; Np = Number of patients randomized to placebo PAH related death or hospitalization for PAH was assessed as a secondary endpoint.
The risk of PAH related death or hospitalization for PAH was reduced by 50% in patients receiving OPSUMIT 10 mg compared to placebo (HR 0.50, 97.5% CI 0.34–0.75; logrank p<0.0001) (Table 4 and Figure 4).
Figure 4 Kaplan-Meier Estimates of the Occurrence of Death due to PAH or Hospitalization for PAH in SERAPHIN Table 4: Summary of Death due to PAH and Hospitalization due to PAH Placebo (N=250) n (%) OPSUMIT 10 mg (N=242) n (%) Death due to PAH or hospitalization for PAH 84 (33.6) 50 (20.7) Component as first event Death due to PAH 5 (2.0) 5 (2.1) Hospitalization for PAH 79 (31.6) 45 (18.6) Treatment with OPSUMIT 10 mg resulted in a placebo-corrected mean increase in 6MWD of 22 meters at Month 6 (97.5% CI 3–41; p=0.0078), with significant improvement in 6MWD by Month 3.
6MWD increased more in patients with worse baseline WHO Functional Class (37 meters and 12 meters placebo-corrected mean increase in WHO FC III/IV and FC I/II, respectively).
The increase in 6MWD achieved with OPSUMIT was maintained for the duration of the study.
Treatment with OPSUMIT 10 mg led to an improvement of at least one WHO Functional Class at Month 6 in 22% of patients compared to 13% of patients treated with placebo.
Figure 2 Figure 3 Figure 4 Long-Term Treatment of PAH In long-term follow-up of patients who were treated with OPSUMIT 10 mg in the placebo-controlled study (N=242) and the open-label extension study, Kaplan-Meier estimates of survival at 1, 2, 5, and 7 years were 95%, 89%, 73%, and 63% respectively.
The median exposure to OPSUMIT was 4.6 years.
These uncontrolled observations do not allow comparison with a group not given OPSUMIT and cannot be used to determine the long term-effect of OPSUMIT on mortality.
HOW SUPPLIED
16 /STORAGE AND HANDLING OPSUMIT ® (macitentan) tablets are 10 mg white, film-coated, bi-convex debossed with “10” on both sides and supplied as follows: 15 count /PVC/ PE/PVDC aluminum foil blisters in carton (NDC 66215-501-15) 30 count white high-density polyethylene bottle in carton (NDC 66215-501-30) Store at 20ºC to 25ºC (68ºF to 77ºF).
Excursions are permitted between 15°C and 30°C (59°F and 86°F).
[See USP Controlled Room Temperature] .
Keep out of reach of children.
GERIATRIC USE
8.5 Geriatric Use Of the total number of subjects in the clinical study of OPSUMIT for PAH, 14% were 65 and over.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
DOSAGE FORMS AND STRENGTHS
3 Tablets: 10 mg, bi-convex film-coated, round, white, and debossed with “10” on both sides.
Tablet: 10 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Endothelin (ET)-1 and its receptors (ET A and ET B ) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation.
In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage.
Macitentan is an endothelin receptor antagonist that inhibits the binding of ET-1 to both ET A and ET B receptors.
Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells.
One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro .
The clinical impact of dual endothelin blockage is unknown.
INDICATIONS AND USAGE
1 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 ( 1.1 ).
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 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%) [see Clinical Studies (14.1) ] .
PEDIATRIC USE
8.4 Pediatric Use The safety and efficacy of OPSUMIT in children have not been established.
PREGNANCY
8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, OPSUMIT may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy.
There are risks to the mother and the fetus associated with pulmonary arterial hypertension in pregnancy [see Clinical Considerations ] .
There are limited data on OPSUMIT use in pregnant women.
Macitentan was teratogenic in rabbits and rats at all doses tested.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the risk to a fetus [see Contraindications (4.1) ] .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor.
Data Animal Data In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities.
Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested.
BOXED WARNING
WARNING: EMBRYO-FETAL TOXICITY Do not administer OPSUMIT to a pregnant female because it may cause fetal harm [see Contraindications (4.1) , Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ].
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 [see Pregnancy Testing in Females of Reproductive Potential (2.2) , Use in Specific Populations (8.3) ].
For all female patients, OPSUMIT is available only through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.2) ] .
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 , 8.3 ).
For all female patients, OPSUMIT is available only through a restricted program called the Macitentan – Containing Products Risk Evaluation and Mitigation Strategy (REMS) ( 5.2 ).
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS ERAs cause hepatotoxicity and liver failure.
Obtain baseline liver enzymes and monitor as clinically indicated ( 5.3 ).
Fluid retention may require intervention ( 5.4 ) Decreases in hemoglobin ( 5.5 ).
Pulmonary edema in patients with pulmonary veno-occlusive disease.
If confirmed, discontinue treatment ( 5.6 ).
Decreases in sperm count have been observed in patients taking ERAs ( 5.7 ).
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 , 8.3) ] .
OPSUMIT is available for females through the Macitentan-Containing Products REMS, a restricted distribution program [see Warnings and Precautions (5.2) ] .
5.2 Macitentan-Containing Products REMS For all females, OPSUMIT is available only through a restricted program called the Macitentan-Containing Products REMS, because of the risk of embryo-fetal toxicity [see Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.3) ] .
Notable requirements of the Macitentan-Containing Products REMS include the following: Prescribers must be certified with the Macitentan-Containing Products REMS by enrolling and completing training.
All females, regardless of reproductive potential, must enroll in the Macitentan-Containing Products REMS 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 [see Use in Specific Populations (8.3) ] .
Pharmacies must be certified with the Macitentan-Containing Products REMS and must only dispense to patients who are authorized to receive OPSUMIT.
Further information is available at www.MacitentanREMS.com or 1-888-572-2934.
Information on Macitentan-Containing Products REMS certified pharmacies or wholesale distributors is available at 1-888-572-2934.
5.3 Hepatotoxicity 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 [see Adverse Reactions (6.2) ] .
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 Fluid Retention Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs.
In the placebo-controlled study of OPSUMIT in PAH, the incidence of edema was 21.9% in the OPSUMIT 10 mg group and 20.5% in the placebo group.
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 OPSUMIT in patients with pulmonary hypertension because of left ventricular dysfunction, more patients in the OPSUMIT group developed significant fluid retention and had more hospitalizations because of worsening heart failure compared to those randomized 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 [see Adverse Reactions (6.2) ] .
Monitor for signs of fluid retention after OPSUMIT initiation.
If clinically significant fluid retention develops, evaluate the patient to determine the cause, such as OPSUMIT or underlying heart failure, and the possible need to discontinue OPSUMIT.
5.5 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) ] .
5.6 Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD) Should signs of pulmonary edema occur, consider the possibility of associated PVOD.
If confirmed, discontinue OPSUMIT.
5.7 Decreased Sperm Counts OPSUMIT, like other ERAs, may have an adverse effect on spermatogenesis.
Counsel men about potential effects on fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1) ] .
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise patient to read FDA-approved patient labeling (Medication Guide).
Embryo-Fetal Toxicity Counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with OPSUMIT and for one month after treatment discontinuation.
Females of reproductive potential must have monthly pregnancy tests and must use reliable methods of contraception while taking OPSUMIT and for one month after discontinuing OPSUMIT [see Use in Specific Populations (8.1) ] .
Macitentan-Containing Products REMS For female patients, OPSUMIT is available only through a restricted program called the Macitentan-Containing Products REMS [see Warnings and Precautions (5.2) ] .
Male patients are not enrolled in the Macitentan-Containing Products REMS.
Patients may choose one highly effective form of contraception (intrauterine devices (IUD), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods).
Patients should be instructed to contact their physician if they suspect they may be pregnant.
Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed.
Inform female patients (and their guardians, if applicable) of the following notable requirements.
Female patients must sign an enrollment form.
Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3) ] .
Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure.
Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber.
Review the Medication Guide and REMS educational materials with female patients.
Lactation Advise women not to breastfeed during treatment with OPSUMIT [see Use in Specific Population (8.2) ] .
Hepatotoxicity Some members of this pharmacological class are hepatotoxic.
Educate patients on signs of hepatotoxicity.
Advise patients that they should contact their doctor if they have unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.
Fluid Retention Educate patients on signs of fluid retention.
Advise patients that they should contact their doctor if they have unusual weight increase or swelling of the ankles or legs.
DOSAGE AND ADMINISTRATION
2 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 ).
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 Obtain a pregnancy test in females of reproductive potential prior to OPSUMIT treatment, monthly during treatment and one month after stopping OPSUMIT.
Initiate treatment with OPSUMIT in females of reproductive potential only after a negative pregnancy test.
[see Boxed Warning , Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.3) ] .