OPSUMIT

Actelion Pharmaceuticals US, Inc.
Actelion Pharmaceuticals Ltd.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese 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: 2013BOXED WARNING 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 Evaluation and Mitigation Strategy (REMS) (5.2). INDICATIONS AND USAGEOPSUMIT® 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). Side EffectsMost 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 INTERACTIONSStrong 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 POPULATIONSNursing mothers: discontinue OPSUMIT or breastfeeding (8.3).

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 OPSUMIT INDICATIONS AND USAGE
  • 1.1 Pulmonary Arterial Hypertension
• 2 OPSUMIT DOSAGE AND ADMINISTRATION
  • 2.1 Recommended Dosage
  • 2.2 Pregnancy Testing in Females of Reproductive Potential
• 3 DOSAGE FORMS AND STRENGTHS
• 4 OPSUMIT 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 OPSUMIT 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 OPSUMIT 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

FULL PRESCRIBING INFORMATION

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:

• 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 [see Use in Specific Populations (8.6)].
• 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.

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)].

5.5 Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)

Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue OPSUMIT.

5.6 Decreased Sperm Counts

Other ERAs have caused adverse effects on spermatogenesis. Counsel men about potential effects on fertility [see Use in Specific Populations (8.6) and Nonclinical Toxicology (13.1)].

6 ADVERSE REACTIONS

Clinically significant adverse reactions that appear in other sections of the labeling include:

• Embryo-fetal Toxicity [see Warnings and Precautions (5.1)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Decrease in Hemoglobin [see Warnings and Precautions (5.4)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Safety data for OPSUMIT were obtained primarily from one placebo-controlled clinical study in 742 patients with PAH (SERAPHIN study) [see Clinical Studies (14)]. The exposure to OPSUMIT in this trial was up to 3.6 years with a median exposure of about 2 years (N=542 for 1 year; N=429 for 2 years; and N=98 for more than 3 years). The overall incidence of treatment discontinuations because of adverse events was similar across OPSUMIT 10 mg and placebo treatment groups (approximately 11%).

Table 2 presents adverse reactions more frequent on OPSUMIT than on placebo by ≥3%.

7 DRUG INTERACTIONS

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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X.

Risk Summary

OPSUMIT may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Macitentan was teratogenic in rabbits and rats at all doses tested. A no-effect dose was not established in either species. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see Contraindications (4.1)].

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.

8.3 Nursing Mothers

It is not known whether OPSUMIT is present in human milk. Macitentan and its metabolites were present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions from macitentan in nursing infants, nursing mothers should discontinue nursing or discontinue OPSUMIT.

8.4 Pediatric use

The safety and efficacy of OPSUMIT in children have not been established.

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.

8.6 Females and Males of Reproductive Potential

Females

Pregnancy Testing: Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with OPSUMIT and monthly pregnancy tests during treatment with OPSUMIT. Advise patients to contact their health care provider if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patients on the potential risk to the fetus [see Boxed Warning and Dosage and Administration (2.2)].

Contraception: Female patients of reproductive potential must use acceptable methods of contraception during treatment with OPSUMIT and for 1 month after treatment with OPSUMIT. 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). If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning].

Males

Testicular effects: Like other endothelin receptor antagonists, OPSUMIT may have an adverse effect on spermatogenesis [see Warnings and Precautions (5.6) and Nonclinical Toxicology (13.1)].

10 OVERDOSAGE

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.

11 DESCRIPTION

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 C₁₉H₂₀Br₂N₆O₄S 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.

12 CLINICAL PHARMACOLOGY

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 prevents 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.

12.2 Pharmacodynamics

Pulmonary Hemodynamics: The clinical efficacy study in patients with pulmonary arterial hypertension assessed hemodynamic parameters in a subset of patients after 6 months of treatment. Patients treated with OPSUMIT 10 mg (N=57) achieved a median reduction of 37% (95% CI 22-49) in pulmonary vascular resistance and an increase of 0.6 L/min/m² (95% CI 0.3-0.9) in cardiac index compared to placebo (N=67).

Cardiac Electrophysiology: In a randomized, placebo-controlled four-way crossover study with a positive control in healthy subjects, repeated doses of macitentan 10 and 30 mg (3 times the recommended dosage) had no significant effect on the QTc interval.

12.3 Pharmacokinetics

The pharmacokinetics of macitentan and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of macitentan are dose proportional over a range from 1 mg to 30 mg after once daily administration.

A cross study comparison shows that the exposures to macitentan and its active metabolite in patients with PAH are similar to those observed in healthy subjects.

Absorption and Distribution

The maximum plasma concentration of macitentan is achieved about 8 hours after oral administration. The absolute bioavailability after oral administration is not known. In a study in healthy subjects, the exposure to macitentan and its active metabolite were unchanged after a high fat breakfast. Macitentan may therefore be taken with or without food.

Macitentan and its active metabolite are highly bound to plasma proteins (>99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. The apparent volumes of distribution (Vss/F) of macitentan and its active metabolite were about 50 L and 40 L respectively in healthy subjects.

Metabolism and Elimination

Following oral administration, the apparent elimination half-lives of macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with a minor contribution of CYP2C19. At steady state in PAH patients, the systemic exposure to the active metabolite is 3-times the exposure to macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. In a study in healthy subjects with radiolabeled macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from feces.

Special Populations

There are no clinically relevant effects of age, sex, or race on the pharmacokinetics of macitentan and its active metabolite.

Renal impairment: Exposure to macitentan and its active metabolite in patients with severe renal impairment (CrCl 15-29 mL/min) compared to healthy subjects was increased by 30% and 60%, respectively. This increase is not considered clinically relevant.

Hepatic impairment: Exposure to macitentan was decreased by 21%, 34%, and 6% and exposure to the active metabolite was decreased by 20%, 25%, and 25% in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, and C), respectively. This decrease is not considered clinically relevant.

Drug Interactions

In vitro studies

At plasma levels obtained with dosing at 10 mg once daily, macitentan has no relevant inhibitory or inducing effects on CYP enzymes, and is neither a substrate nor an inhibitor of the multi-drug resistance protein (P-gp, MDR-1). Macitentan and its active metabolite are neither substrates nor inhibitors of the organic anion transporting polypeptides (OATP1B1 and OATP1B3) and do not significantly interact with proteins involved in hepatic bile salt transport, i.e., the bile salt export pump (BSEP) and the sodium-dependent taurocholate co-transporting polypeptide (NTCP).

In vivo studies

Effect of other drugs on macitentan: The effect of other drugs on macitentan and its active metabolite are studied in healthy subjects and are shown in Figure 1 below.

Figure 1

Effects of other strong CYP3A4 inhibitors such as ritonavir on macitentan were not studied, but are likely to result in an increase in macitentan exposure at steady state similar to that seen with ketoconazole [see Drug Interactions (7.2)].

Effect of macitentan on other drugs

Warfarin: Macitentan once daily dosing did not alter the exposure to R- and S-warfarin or their effect on international normalized ratio (INR).

Sildenafil: At steady-state, the exposure to sildenafil 20 mg t.i.d. increased by 15% during concomitant administration of macitentan 10 mg once daily. This change is not considered clinically relevant.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Carcinogenicity studies of 2 years' duration did not reveal any carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and female mice, respectively, and 8.3- and 42-fold in male and female rats, respectively.

Mutagenesis: Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in rats.

Impairment of Fertility: Treatment of juvenile rats from postnatal Day 4 to Day 114 led to reduced body weight gain and testicular tubular atrophy at exposures 7-fold the human exposure. Fertility was not affected.

Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not affect male or female fertility at exposures ranging from 19- to 44-fold the human exposure, respectively, and had no effect on sperm count, motility, and morphology in male rats. No testicular findings were noted in mice after treatment up to 2 years.

13.2 Animal Toxicology

In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. Intimal thickening of coronary arteries was observed at 17-fold the human exposure after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is considered not relevant for humans.

There were no adverse liver findings in long-term studies conducted in mice, rats, and dogs at exposures of 12- to 116-fold the human exposure.

14 CLINICAL STUDIES

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.

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 eventNo 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

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

OPSUMIT tablets are 10 mg white, film-coated, bi-convex debossed with "10" on one side 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 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Embryo-Fetal Toxicity

Instruct patients on the risk of fetal harm when OPSUMIT is used in pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Instruct females of reproductive potential to use effective contraception and to contact her physician if they suspect they may be pregnant. Female patients must enroll in the OPSUMIT REMS program.

OPSUMIT REMS Program

For female patients, OPSUMIT is available only through a restricted program called the OPSUMIT REMS Program [see Warnings and Precautions (5.2)]. Male patients are not enrolled in the OPSUMIT REMS.

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 (8.6)].

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.

Decrease in Hemoglobin

Advise patients on the importance of hemoglobin testing.

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.

Administration

Patients should be advised not to split, crush, or chew tablets.

Manufactured for:
Actelion Pharmaceuticals US, Inc.
5000 Shoreline Court, Ste. 200
South San Francisco, CA 94080, USA

© 2013 Actelion Pharmaceuticals US, Inc. All rights reserved.

ACT20131018

Medication Guide

OPSUMIT (OP-sum-it)
(macitentan)
tablets

Read this Medication Guide for Opsumit before you start taking Opsumit and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Opsumit?

• Serious birth defects.
  Opsumit can cause serious birth defects if taken during pregnancy.
  • Females must not be pregnant when they start taking Opsumit or become pregnant during treatment with Opsumit.
  • Females who are able to get pregnant must have a negative pregnancy test before beginning treatment with Opsumit, each month during treatment with Opsumit and 1 month after stopping Opsumit. Talk to your healthcare provider about your menstrual cycle. Your healthcare provider will decide when to do the tests, and order the tests for you depending on your menstrual cycle.
    • Females who are able to get pregnant are females who:
      • Have entered puberty, even if they have not started their period, and
      • Have a uterus, and
      • Have not gone through menopause (have not had a period for at least 12 months for natural reasons, or who have had their ovaries removed)
    • Females who are not able to get pregnant are females who:
      • Have not yet entered puberty, or
      • Do not have a uterus, or
      • Have gone through menopause (have not had a period for at least 12 months for natural reasons, or who have had their ovaries removed)
  Females who are able to get pregnant must use two acceptable forms of birth control during treatment with Opsumit, and for one month after stopping Opsumit because the medicine may still be in the body.
  • If you have had a tubal sterilization, have a progesterone implant, or have an IUD (intrauterine device), these methods can be used alone and no other form of birth control is needed.
  • Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable birth control that you may use to prevent pregnancy during treatment with Opsumit.
  • If you decide that you want to change the form of birth control that you use, talk with your healthcare provider or gynecologist to be sure that you choose another acceptable form of birth control.
  See the chart below for Acceptable Birth Control Options during treatment with Opsumit.
  
  • Do not have unprotected sex. Talk to your healthcare provider or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your healthcare provider may talk with you about using emergency birth control.
  • Tell your healthcare provider right away if you miss a menstrual period or think you may be pregnant for any reason.
  If you are the parent or caregiver of a female child who started taking Opsumit before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your healthcare provider right away if you notice that she is developing breast buds or any pubic hair. Your healthcare provider should decide if your child has reached puberty. Your child may reach puberty before having her first menstrual period.
  Females can only receive Opsumit through a restricted program called the Opsumit Risk Evaluation and Mitigation Strategy (REMS) Program. If you are a female who can get pregnant, you must talk to your healthcare provider, understand the benefits and risks of Opsumit, and agree to all of the instructions in the Opsumit REMS Program.
  Males can receive Opsumit without taking part in the Opsumit REMS Program.

What is Opsumit?

• Opsumit is a prescription medicine used to treat pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of your lungs.
• Opsumit can improve your ability to exercise, improve some of your symptoms, and help slow down the progression of your disease. Opsumit can also lower your chance of being hospitalized for PAH.
• It is not known if Opsumit is safe and effective in children.

Who should not take Opsumit?

Do not take Opsumit if you are pregnant, plan to become pregnant, or become pregnant during treatment with Opsumit. Opsumit can cause serious birth defects (see the Medication Guide section above called "What is the most important information I should know about Opsumit?").

Tell your healthcare provider about all your medical conditions and all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Opsumit and other medicines may affect each other causing side effects. Do not start any new medicine until you check with your healthcare provider.

Especially tell your healthcare provider if you take an HIV medicine.

How should I take Opsumit?

Opsumit will be mailed to you by a specialty pharmacy. Your healthcare provider will give you complete details.

• Take Opsumit exactly as your healthcare provider tells you to take it. Do not stop taking Opsumit unless your healthcare provider tells you.
• You can take Opsumit with or without food.
• Do not split, crush, or chew Opsumit tablets.
• If you take too much Opsumit, call your healthcare provider or go to the nearest hospital emergency room right away.
• If you miss a dose of Opsumit, take it as soon as you remember that day. Take the next dose at your regular time. Do not take 2 doses at the same time to make up for a missed dose.

What should I avoid while taking Opsumit?

• Do not get pregnant while taking Opsumit. See the serious birth defects section of the Medication Guide above called "What is the most important information I should know about Opsumit?" If you miss a menstrual period, or think you might be pregnant, call your healthcare provider right away.
• It is not known if Opsumit passes into your breastmilk. You should not breastfeed if you take Opsumit. Talk to your healthcare provider about the best way to feed your baby if you take Opsumit.

What are the possible side effects of Opsumit?

Opsumit can cause serious side effects, including:

• Serious birth defects. See "What is the most important information I should know about Opsumit?"
• Some medicines that are like Opsumit can cause liver problems. Your healthcare provider should do blood tests to check your liver before you start taking Opsumit. Tell your healthcare provider if you have any of the following symptoms of liver problems while taking Opsumit.

  nausea or vomiting pain in the upper right stomach tiredness loss of appetite

  yellowing of your skin or whites of your eyes dark urine fever itching

• Low red blood cell levels (anemia) can occur with Opsumit treatment, usually during the first weeks after starting therapy. In some cases a blood transfusion may be needed, but this is not common. Your healthcare provider will do blood tests to check your red blood cells before starting Opsumit. Your healthcare provider may also need to do these tests during treatment with Opsumit.
• Sperm count reduction. Reduced sperm counts have been observed in some men taking a medicine similar to Opsumit, an effect which might impair their ability to father a child. Tell your healthcare provider if remaining fertile is important to you.

The most common side effects of Opsumit are:

• Stuffy nose or sore throat
• Irritation of the airways (bronchitis)
• headache
• Flu
• Urinary tract infection

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Opsumit. For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Opsumit?

• Store Opsumit tablets at room temperature between 68°F and 77°F (20°C and 25°C).
• Keep Opsumit and all medicines out of the reach of children.

General information about Opsumit

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Opsumit for a condition for which it was not prescribed. Do not give Opsumit to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Opsumit. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Opsumit that is written for health professionals. For more information, call 1-866-228-3546, or visit www.OPSUMIT.com.

What are the ingredients in Opsumit?

Active ingredient: macitentan

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.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Actelion Pharmaceuticals US, Inc.
5000 Shoreline Court, Ste. 200
South San Francisco, CA 94080, USA
Issued: October 2013
ACT20131018

© 2013 Actelion Pharmaceuticals US, Inc. All rights reserved.

PRINCIPAL DISPLAY PANEL - 10 mg Bottle Carton

NDC 66215-501-30
30 tablets

Opsumit_®
macitentan tablets

10 mg

Rx only

Dispense the
accompanying
Medication Guide
to each patient

ACTELION