OPSUMIT 2.5mg dispersible tablets medication leaflet

Opsumit 2.5 mg dispersible tablets

Each dispersible tablet contains 2.5 mg macitentan.

Each dispersible tablet contains approximately 25 mg of isomalt.

For the full list of excipients, see section 6.1.

Dispersible tablet.

Round (9 mm) white to almost white dispersible tablet, debossed with a “2.5” on one side and with“Mn” on the other side.

Opsumit, as monotherapy or in combination, is indicated for the long-term treatment of pulmonaryarterial hypertension (PAH) in paediatric patients aged 2 years to less than 18 years with WHO

Functional Class (FC) II to III (see section 5.1).

Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.

Paediatric population (aged ≥ 2 years to less than 18 years)

The recommended daily dose of Opsumit is based on body weight (Table 1). Opsumit should be takenevery day at about the same time.

Table 1: Dosing regimen based on body weight

Body weight (kg) Daily dose Recommended number of tablets to be dispersed≥ 10 and < 20 5 mg 2 × 2.5 mg≥ 20 and < 40 7.5 mg 3 × 2.5 mg≥ 40 10 mg 4 × 2.5 mg*

*Opsumit is also available as a 10 mg film-coated tablet. Opsumit administered in the form ofone 10 mg film-coated tablet is bioequivalent to four 2.5 mg dispersible tablets. Therefore,one film-coated tablet may be used as a direct replacement for paediatric patients who weigh at least40 kg and are aged 2 years and older (see section 5.2). Please refer to the Opsumit film-coated tablets

Summary of Product Characteristics.

If the patient misses a dose of Opsumit, administer it as soon as possible and then take the next dose atthe regularly scheduled time. The patient should not take two doses at the same time if a dose has beenmissed.

No dose adjustment is required in patients over the age of 65 years (see section 5.2).

Based on pharmacokinetic (PK) data, no dose adjustment is required in patients with mild, moderateor severe hepatic impairment (see sections 4.4 and 5.2). However, there is no clinical experience withthe use of macitentan in PAH patients with moderate or severe hepatic impairment. Opsumit must notbe initiated in patients with severe hepatic impairment, or clinically significant elevated hepaticaminotransferases (greater than 3 times the Upper Limit of Normal (> 3 × ULN); see sections 4.3 and4.4).

Based on PK data, no dose adjustment is required in patients with renal impairment. There is noclinical experience with the use of macitentan in PAH patients with severe renal impairment. The useof Opsumit is not recommended in patients undergoing dialysis (see sections 4.4 and 5.2).

Dosing and efficacy of macitentan in children below 2 years of age have not been established.

Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on aposology can be made.

Opsumit should be taken orally once a day with or without food.

Opsumit dispersible tablet(s) must be dispersed in room temperature liquids and are to be taken as anoral suspension only. The oral suspension must be prepared and administered using either a spoon or asmall glass. Care should be taken to ensure the entire dose of medicine has been taken. If notadministered right away the medicine should be discarded and a new dose of medicine should beprepared. Hands must be thoroughly washed and dried before and after preparation of the medicine(see section 6.6).

Administration by a spoon

The prescribed daily dose of dispersible tablet(s) should be added to room temperature drinking waterin a spoon to form a white cloudy liquid. The liquid can be gently stirred for 1 to 3 minutes using aknife tip to speed up dissolution. Either administer the medicine to the patient right away or mix itfurther with a small portion of apple sauce or yoghurt to aid with administration. A little more water orapple sauce or yoghurt should be added to the spoon and administered to the patient to make sure theentire dose of medicine has been taken.

Alternatively, instead of drinking water, the oral suspension can be prepared in orange juice, applejuice or skimmed milk.

Administration by a glass

The prescribed daily dose of dispersible tablet(s) should be placed in a small glass containing a smallvolume (maximum 100 mL) of room temperature drinking water to form a white cloudy liquid. Theliquid can be gently stirred with a spoon for 1 to 2 minutes. Administer the medicine to the patientright away. A little more water should be added to the glass and stirred with the same spoon to re-suspend any remaining medicine. The entire contents of the glass should be administered to the patientto make sure all the medicine has been taken.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Pregnancy (see section 4.6).

- Women of childbearing potential who are not using reliable contraception (see sections 4.4 and4.6).

- Breastfeeding (see section 4.6).

- Patients with severe hepatic impairment (with or without cirrhosis) (see section 4.2).

- Baseline values of hepatic aminotransferases (aspartate aminotransferases (AST) and/or alanineaminotransferases (ALT) > 3 × ULN) (see sections 4.2 and 4.4).

The benefit/risk balance of macitentan has not been established in patients with WHO class Ifunctional status of pulmonary arterial hypertension.

Elevations of liver aminotransferases (AST, ALT) have been associated with PAH and with endothelinreceptor antagonists (ERAs). Opsumit is not to be initiated in patients with severe hepatic impairmentor elevated aminotransferases (> 3 × ULN) (see sections 4.2 and 4.3) and is not recommended inpatients with moderate hepatic impairment. Liver enzyme tests should be obtained prior to initiation of

Opsumit.

Patients should be monitored for signs of hepatic injury and monthly monitoring of ALT and AST isrecommended. If sustained, unexplained, clinically relevant aminotransferase elevations occur, or ifelevations are accompanied by an increase in bilirubin > 2 × ULN, or by clinical symptoms of liverinjury (e.g., jaundice), Opsumit treatment should be discontinued.

Reinitiation of Opsumit may be considered following the return of hepatic enzyme levels to within thenormal range in patients who have not experienced clinical symptoms of liver injury. The advice of ahepatologist is recommended.

Decrease in haemoglobin concentrations has been associated with endothelin receptor antagonists(ERAs) including macitentan (see section 4.8). In placebo-controlled studies, macitentan-relateddecreases in haemoglobin concentration were not progressive, stabilised after the first 4-12 weeks oftreatment and remained stable during chronic treatment. Cases of anaemia requiring blood celltransfusion have been reported with macitentan and other ERAs. Initiation of Opsumit is notrecommended in patients with severe anaemia. It is recommended that haemoglobin concentrations bemeasured prior to initiation of treatment and tests repeated during treatment as clinically indicated.

Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used inpatients with pulmonary veno-occlusive disease. Consequently, if signs of pulmonary oedema occurwhen macitentan is administered in patients with PAH, the possibility of pulmonary veno-occlusivedisease should be considered.

Opsumit treatment should only be initiated in women of childbearing potential when the absence ofpregnancy has been verified, appropriate advice on contraception provided, and reliable contraceptionis practised (see sections 4.3 and 4.6). Women should not become pregnant for 1 month afterdiscontinuation of Opsumit. Monthly pregnancy tests during treatment with Opsumit arerecommended to allow the early detection of pregnancy.

In the presence of strong CYP3A4 inducers reduced efficacy of macitentan could occur. Thecombination of macitentan with strong CYP3A4 inducers (e.g., rifampicin, St. John’s wort,carbamazepine, and phenytoin) should be avoided (see section 4.5).

Caution should be exercised when macitentan is administered concomitantly with strong CYP3A4inhibitors (e.g., itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone,ritonavir, and saquinavir) (see section 4.5).

Caution should be exercised when macitentan is administered concomitantly with moderate dualinhibitors of CYP3A4 and CYP2C9 (e.g., fluconazole and amiodarone) (see section 4.5).

Caution should also be exercised when macitentan is administered concomitantly with both amoderate CYP3A4 inhibitor (e.g., ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil)and moderate CYP2C9 inhibitor (e.g., miconazole, piperine) (see section 4.5).

Patients with renal impairment may run a higher risk of experiencing hypotension and anaemia duringtreatment with macitentan. Therefore, monitoring of blood pressure and haemoglobin should beconsidered. There is no clinical experience with the use of macitentan in PAH patients with severerenal impairment. Caution is recommended in this population. There is no experience with the use ofmacitentan in patients undergoing dialysis, therefore Opsumit is not recommended in this population(see sections 4.2 and 5.2).

Opsumit dispersible tablets contain isomalt. Patients with rare hereditary problems of fructoseintolerance should not take this medicine.

Other excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

The cytochrome P450 CYP3A4 is the main enzyme involved in the metabolism of macitentan and inthe formation of its active metabolite, with minor contribution from CYP2C8, CYP2C9, and

CYP2C19 enzymes (see section 5.2). Macitentan and its active metabolite do not have clinicallyrelevant inhibitory or inducing effects on cytochrome P450 enzymes.

Macitentan and its active metabolite are not inhibitors of hepatic or renal uptake transporters atclinically relevant concentrations, including the organic anion transporting polypeptides (OATP1B1and OATP1B3). Macitentan and its active metabolite are not relevant substrates of OATP1B1 and

OATP1B3 but enter the liver by passive diffusion.

Macitentan and its active metabolite are not inhibitors of hepatic or renal efflux pumps at clinicallyrelevant concentrations, including the multi-drug resistance protein (P-gp, MDR-1) and multidrug andtoxin extrusion transporters (MATE1 and MATE2-K). Macitentan is not a substrate for P-gp/MDR-1.

At clinically relevant concentrations, macitentan and its active metabolite do not interact with proteinsinvolved in hepatic bile salt transport, i.e., the bile salt export pump (BSEP) and the sodium-dependenttaurocholate co-transporting polypeptide (NTCP).

Concomitant treatment with rifampicin 600 mg daily, a potent inducer of CYP3A4, reduced thesteady-state exposure to macitentan by 79% but did not affect the exposure to the active metabolite.

Reduced efficacy of macitentan in the presence of a potent inducer of CYP3A4 such as rifampicinshould be considered. The combination of macitentan with strong CYP3A4 inducers should beavoided (see section 4.4).

Ketoconazole

In the presence of ketoconazole 400 mg once daily, a strong CYP3A4 inhibitor, exposure tomacitentan increased approximately 2-fold. The predicted increase was approximately 3-fold in thepresence of ketoconazole 200 mg twice daily using physiologically based pharmacokinetic (PBPK)modelling. The uncertainties of such modelling should be considered. Exposure to the activemetabolite of macitentan was reduced by 26%. Caution should be exercised when macitentan isadministered concomitantly with strong CYP3A4 inhibitors (see section 4.4).

Fluconazole

In the presence of fluconazole 400 mg daily, a moderate dual inhibitor of CYP3A4 and CYP2C9,exposure to macitentan may increase approximately 3.8-fold based on PBPK modelling. However,there was no clinically relevant change in exposure to the active metabolite of macitentan. Theuncertainties of such modelling should be considered. Caution should be exercised when macitentan isadministered concomitantly with moderate dual inhibitors of CYP3A4 and CYP2C9 (e.g., fluconazoleand amiodarone) (see section 4.4).

Caution should also be exercised when macitentan is administered concomitantly with both amoderate CYP3A4 inhibitor (e.g., ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil)and moderate CYP2C9 inhibitor (e.g., miconazole, piperine) (see section 4.4).

Macitentan given as multiple doses of 10 mg once daily had no effect on exposure to S-warfarin(CYP2C9 substrate) or R-warfarin (CYP3A4 substrate) after a single dose of 25 mg warfarin. Thepharmacodynamic effect of warfarin on International Normalised Ratio (INR) was not affected bymacitentan. The pharmacokinetics of macitentan and its active metabolite were not affected bywarfarin.

Sildenafil

At steady-state, the exposure to sildenafil 20 mg three times a day was increased by 15% duringconcomitant administration of macitentan 10 mg once daily. Sildenafil, a CYP3A4 substrate, did notaffect the pharmacokinetics of macitentan, while there was a 15% reduction in the exposure to theactive metabolite of macitentan. These changes are not considered clinically relevant. In aplacebo-controlled trial in adult patients with PAH, the efficacy and safety of macitentan incombination with sildenafil were demonstrated.

Cyclosporine A

Concomitant treatment with cyclosporine A 100 mg twice daily, a combined CYP3A4 and OATPinhibitor, did not alter the steady-state exposure to macitentan and its active metabolite to a clinicallyrelevant extent.

Macitentan 10 mg once daily did not affect the pharmacokinetics of an oral contraceptive(norethisterone 1 mg and ethinyl estradiol 35 µg).

Breast cancer resistance protein (BCRP) substrate drugs

Macitentan 10 mg once daily did not affect the pharmacokinetics of a BCRP substrate drug (riociguat1 mg; rosuvastatin 10 mg).

Interaction studies have only been performed in adults.

Opsumit treatment should only be initiated in women of childbearing potential when the absence ofpregnancy has been verified, appropriate advice on contraception provided, and reliable contraceptionis practised (see sections 4.3 and 4.4). Women should not become pregnant for 1 month afterdiscontinuation of Opsumit. Monthly pregnancy tests during treatment with Opsumit arerecommended to allow the early detection of pregnancy.

There are no data from the use of macitentan in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). The potential risk for humans is still unknown. Opsumit iscontraindicated during pregnancy and in women of childbearing potential who are not using reliablecontraception (see section 4.3).

It is unknown whether macitentan is excreted in human milk. In rats, macitentan and its metabolitesare excreted into milk during lactation (see section 5.3). A risk to the breastfeeding child cannot beexcluded. Opsumit is contraindicated during breastfeeding (see section 4.3).

The development of testicular tubular atrophy in male animals was observed after treatment withmacitentan (see section 5.3). Decreases in sperm count have been observed in patients taking ERAs.

Macitentan, like other ERAs, may have an adverse effect on spermatogenesis in men.

Macitentan has minor influence on the ability to cycle, drive and use machines. No studies on theeffects on the ability to drive and use machines have been performed. However, undesirable effectsmay occur (e.g., headache, hypotension) that may influence the ability to cycle, drive and usemachines (see section 4.8).

The most commonly reported adverse reactions in the SERAPHIN study were nasopharyngitis (14%),headache (13.6%) and anaemia (13.2%, see section 4.4).

The safety of macitentan has been evaluated in a long-term placebo-controlled trial of 742 adult andadolescent patients with symptomatic PAH (SERAPHIN study). The mean treatment duration was103.9 weeks in the macitentan 10 mg group, and 85.3 weeks in the placebo group. Adverse reactionsassociated with macitentan obtained from this clinical study are tabulated below. Post-marketingadverse reactions are also included.

Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon(≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot beestimated from the available data).

System organ class Frequency Adverse reaction

Infections and infestations Very common Nasopharyngitis

Very common Bronchitis

Common Pharyngitis

Common Influenza

Common Urinary tract infection

Blood and lymphatic system Very common Anaemia, haemoglobindisorders decrease5

Common Leukopenia6

Common Thrombocytopenia7

Immune system disorders Uncommon Hypersensitivity reactions (e.g.,angioedema, pruritus, rash)1

Nervous system disorders Very common Headache

Vascular disorders Common Hypotension2, flushing

Respiratory, thoracic and Common Nasal congestion1mediastinal disorders

Hepatobiliary disorders Common Aminotransferase elevations4

Reproductive system and Common Increased uterine bleeding8breast disorders

General disorders and Very common Oedema, fluid retention3administration site conditions1 Data derived from pooled placebo-controlled studies.8 Includes PTs of heavy menstrual bleeding, abnormal uterine bleeding, intermenstrual bleeding,uterine/vaginal haemorrhage, polymennorhoea and menstruation irregular. Frequency based on exposurein females.

Description of selected adverse reactions2 Hypotension has been associated with the use of ERAs including macitentan. In SERAPHIN, along-term double-blind study in patients with PAH, hypotension was reported for 7.0% and 4.4% ofpatients on macitentan 10 mg and placebo, respectively. This corresponded to3.5 events/100 patient-years on macitentan 10 mg compared to 2.7 events/100 patient-years onplacebo.

3 Oedema/fluid retention has been associated with the use of ERAs including macitentan. In

SERAPHIN, a long-term double-blind study in patients with PAH, the incidence of oedema AEs in themacitentan 10 mg and placebo treatment groups was 21.9% and 20.5%, respectively. In a double-blindstudy in adult patients with idiopathic pulmonary fibrosis, the incidence of peripheral oedema AEs inthe macitentan and placebo treatment groups was 11.8% and 6.8%, respectively. In two double-blindclinical studies in adult patients with digital ulcers associated with systemic sclerosis, the incidences ofperipheral oedema AEs ranged from 13.4% to 16.1% in the macitentan 10 mg groups and from 6.2%to 4.5% in the placebo groups.

Laboratory abnormalities4 Liver aminotransferases

The incidence of aminotransferase elevations (ALT/AST) > 3 × ULN was 3.4% on macitentan 10 mgand 4.5% on placebo in SERAPHIN, a double-blind study in adult patients with PAH. Elevations> 5 × ULN occurred in 2.5% of patients on macitentan 10 mg versus 2% of patients on placebo.

In SERAPHIN, a double-blind study in adult patients with PAH, macitentan 10 mg was associatedwith a mean decrease in haemoglobin versus placebo of 1 g/dL. A decrease from baseline inhaemoglobin concentration to below 10 g/dL was reported in 8.7% of patients treated with macitentan10 mg and 3.4% of placebo-treated patients.

In SERAPHIN, a double-blind study in adult patients with PAH, macitentan 10 mg was associatedwith a decrease in mean leucocyte count from baseline of 0.7 × 109/L versus no change in placebo-treated patients.

In SERAPHIN, a double-blind study in adult patients with PAH, macitentan 10 mg was associatedwith a decrease in mean platelet count of 17 × 109/L, versus a mean decrease of 11 × 109/L inplacebo-treated patients.

Of the 742 patients who participated in the pivotal SERAPHIN double-blind study, 550 patientsentered a long-term open-label (OL) extension study. (The OL cohort included 182 patients whocontinued on macitentan 10 mg and 368 patients who received placebo or macitentan 3 mg andcrossed over to macitentan 10 mg.)

Long-term follow-up of these 550 patients for a median exposure of 3.3 years and a maximumexposure of 10.9 years showed a safety profile that was consistent as described above during the

SERAPHIN double-blind phase.

Paediatric population (aged ≥ 2 years to less than 18 years)

The safety of macitentan was evaluated in TOMORROW, a Phase 3 study in paediatric patients with

PAH. A total of 72 patients aged ≥ 2 years to less than 18 years were randomised and received

Opsumit. The mean age at enrolment was 10.5 years (range 2.1 years-17.9 years). The medianduration of treatment in the randomised study was 168.4 weeks (range 12.9 weeks-312.4 weeks) in the

Opsumit arm.

Overall, the safety profile in this paediatric population was consistent with that observed in the adultpopulation. In addition to the adverse reactions tabulated above, the following paediatric adversereactions were reported: upper respiratory tract infection (31.9%), rhinitis (8.3%), and gastroenteritis(11.1%).

Paediatric population (aged ≥ 1 month to less than 2 years)

An additional 11 patients, aged ≥ 1 month to less than 2 years old were enroled to receive Opsumitwithout randomisation, 9 patients from the open-label arm of the TOMORROW study and 2 Japanesepatients from the PAH3001 study. At enrolment, the age range of the patients from the TOMORROWstudy was 1.2 years to 1.9 years and the median duration of treatment was 37.1 weeks (range 7.0-72.9weeks). At enrolment, the ages of the 2 patients from PAH3001 were 21 months and 22 months.

Overall, the safety profile in this paediatric population was consistent with that observed in the adultpopulation and paediatric population aged ≥ 2 years to less than 18 years, however, very limitedclinical safety data are available to establish a robust safety conclusion in paediatric population below2 years.

The safety of macitentan in children below 2 years of age has not been established (see section 4.2).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Macitentan has been administered as a single dose of up to 600 mg to healthy adult subjects. Adversereactions of headache, nausea, and vomiting were observed. In the event of an overdose, standardsupportive measures must be taken, as required. Due to the high degree of protein binding ofmacitentan, dialysis is unlikely to be effective.

Pharmacotherapeutic group: anti-hypertensives, anti-hypertensives for pulmonary arterialhypertension. ATC code: C02KX04.

Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of effects such asvasoconstriction, 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 organdamage.

Macitentan is an orally active potent endothelin receptor antagonist, active on both ETA and ETBreceptors and approximately 100-fold more selective for ETA as compared to ETB in vitro. Macitentandisplays high affinity and sustained occupancy of the ET receptors in human pulmonary arterialsmooth muscle cells. This prevents endothelin-mediated activation of second messenger systems thatresult in vasoconstriction and smooth muscle cell proliferation.

A multi-centre, double-blind, placebo-controlled, parallel-group, event-driven, Phase 3 outcome study(AC-055-302/SERAPHIN) was conducted in 742 patients with symptomatic PAH, who wererandomised to three treatment groups (placebo [N = 250], 3 mg [N = 250] or 10 mg [N = 242] ofmacitentan once daily), to assess the long-term effect on morbidity or mortality.

At baseline, the majority of enroled patients (64%) were treated with a stable dose of specific therapyfor PAH, either oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostanoids (6%).

The primary endpoint was the time to first occurrence of a morbidity or mortality event, up to the endof double-blind treatment, defined as death, or atrial septostomy, or lung transplantation, or initiationof intravenous (i.v.) or subcutaneous (s.c.) prostanoids, or other worsening of PAH. Other worseningof PAH was defined as the presence of all of the three following components: a sustained decrease in6-minute walk distance (6MWD) of at least 15% from baseline; worsening of PAH symptoms(worsening of WHO FC or right heart failure); and need for new treatment for PAH. All events wereconfirmed by an independent adjudication committee, blinded to treatment allocation.

All patients were followed up to end-of-study (EOS) for vital status. EOS was declared when thepredefined number of primary endpoint events was reached. In the period between end-of-treatment(EOT) and EOS, patients could receive open-label macitentan 10 mg or alternative PAH therapy. Theoverall median double-blind treatment duration was 115 weeks (up to a maximum of 188 weeks onmacitentan).

The mean age of all patients was 46 years (range 12-85 years of age, including 20 patients below 18,706 patients between 18-74 years, and 16 patients aged 75 and older) with the majority of subjectsbeing Caucasian (55%) 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 aetiology in the study population (57%), followedby PAH due to connective tissue disorders (31%), PAH associated with corrected simple congenitalheart disease (8%), and PAH associated with other aetiologies (medicinal products and toxins [3%]and HIV [1%]).

Treatment with macitentan 10 mg resulted in a 45% risk reduction (hazard ratio [HR] 0.55; 97.5% CI:0.39 to 0.76; logrank p < 0.0001) of the composite morbidity-mortality endpoint up to EOT whencompared to placebo [Figure 1 and Table 2]. The treatment effect was established early and wassustained.

Efficacy of macitentan 10 mg on the primary endpoint was consistent across subgroups of age, sex,ethnic origin, geographical region, aetiology, by monotherapy or in combination with another PAHtherapy and by WHO FC (I/II and III/IV).

Figure 1 Kaplan-Meier estimates of the first morbidity-mortality event in SERAPHIN

Table 2: Summary of outcome events

Patients with events Treatment comparison:macitentan 10 mg vs placebo

Endpoints &

Macitentan Absolute Relative riskstatistics Placebo HR a Logrank10 mg risk reduction(N = 250) (97.5% CI) p-value(N = 242) reduction (97.5% CI)

Morbidity-45% 0.55mortality 53% 37% 16% < 0.0001(24%; 61%) (0.39; 0.76)event b

Death c36% 0.6419 (7.6%) 14 (5.8%) 2% 0.20n (%) (−42%; 71%) (0.29; 1.42)

Worseningof PAH 93 (37.2%) 59 (24.4%) 13%n (%) 49%0.51i.v./s.c. (27%; 65%) < 0.0001(0.35; 0.73)prostanoid6 (2.4%) 1 (0.4%) 2%initiationn (%)a = based on Cox’s Proportional Hazards Modelb = % of patients with an event at 36 months = 100 × (1 - KM estimate)c = all cause death up to EOT regardless of prior worsening

The number of deaths of all causes up to EOS on macitentan 10 mg was 35 versus 44 on placebo (HR0.77; 97.5% CI: 0.46 to 1.28).

The risk of PAH-related death or hospitalisation for PAH up to EOT was reduced by 50% (HR 0.50;97.5% CI: 0.34 to 0.75; logrank p < 0.0001) in patients receiving macitentan 10 mg (50 events)compared to placebo (84 events). At 36 months, 44.6% of patients on placebo and 29.4% of patientson macitentan 10 mg (Absolute Risk Reduction = 15.2%) had been hospitalised for PAH or died froma PAH-related cause.

Exercise capacity was evaluated as a secondary endpoint. Treatment with macitentan 10 mg at

Month 6 resulted in a placebo-corrected mean increase in 6MWD of 22 meters (97.5% CI: 3 to 41;p = 0.0078). Evaluation of 6MWD by functional class resulted in a placebo-corrected mean increasefrom baseline to Month 6 in FC III/IV patients of 37 meters (97.5% CI: 5 to 69) and in FC I/II of 12meters (97.5% CI: 8 to 33). The increase in 6MWD achieved with macitentan was maintained for theduration of the study.

Treatment with macitentan 10 mg at Month 6 led to a 74% higher chance of WHO FC improvementrelative to placebo (risk ratio 1.74; 97.5% CI: 1.10 to 2.74; p = 0.0063).

Macitentan 10 mg improved quality of life assessed by the SF-36 questionnaire.

Haemodynamic parameters were assessed in a subset of patients (placebo [N = 67], macitentan 10 mg[N = 57]) after 6 months of treatment. Patients treated with macitentan 10 mg achieved a medianreduction of 36.5% (97.5% CI: 21.7 to 49.2%) in pulmonary vascular resistance and an increase of0.58 L/min/m2 (97.5% CI: 0.28 to 0.93 L/min/m2) in cardiac index compared to placebo.

In long-term follow-up of 242 patients who were treated with macitentan 10 mg in the double-blind(DB) phase of the SERAPHIN study, 182 of which continued with macitentan in the open-label (OL)extension study (SERAPHIN OL) (DB/OL cohort), Kaplan-Meier estimates of survival at 1, 2, 5, 7and 9 years were 95%, 89%, 73%, 63% and 53%, respectively. The median follow-up time was5.9 years.

Efficacy in paediatric population is mainly based in an extrapolation exercise based upon exposure-matching to the adult efficacious dose range given the similarity of the disease in children and adults,as well as on supportive efficacy and safety data from the TOMORROW phase 3 study describedbelow.

A multi-centre, open-label, randomised, Phase 3 study with an open-label single-arm extension period(TOMORROW) was conducted to assess pharmacokinetics, efficacy and safety of macitentan inpaediatric patients with symptomatic PAH.

The primary endpoint was the characterisation of pharmacokinetics (see section 5.2).

The key secondary combined endpoint was the time to first Clinical Events Committee (CEC)confirmed disease progression occurring between randomisation and the end of the core period(EOCP) visit defined as, deaths (all causes), or atrial septostomy or Potts’ anastomosis, or registrationon lung transplant list, or hospitalisation due to worsening PAH or clinical worsening of PAH. Clinicalworsening of PAH was defined as: need for, or initiation of new PAH-specific therapy or IV diureticsor continuous oxygen use AND at least 1 of the following: worsening in WHO FC, or new occurrenceor worsening of syncope, or new occurrence or worsening of at least 2 PAH symptoms or newoccurrence or worsening of signs of right heart failure not responding to oral diuretics.

Other secondary endpoints included time to first CEC-confirmed hospitalisation for PAH, time to

CEC-confirmed death due to PAH both between randomisation and EOCP, time to all-cause deathbetween randomisation and EOCP, change in WHO FC, and N-terminal prohormone of brainnatriuretic peptide (NT-proBNP) data.

Paediatric population (aged ≥ 2 years to less than 18 years)

A total of 148 patients aged ≥ 2 years to < 18 years were randomised 1:1 to receive either macitentanor Standard of Care (SoC). SoC included PAH non-specific treatment and/or up to 2 PAH-specificmedications (including another ERA) and excluding macitentan and IV/SC prostanoids. The mean agewas 9.8 years (range 2.1 years-17.9 years), with 35 (23.6%) aged ≥ 2 to <6 years, 61 (41.2%) aged≥ 6 to < 12 years, and 52 (35.1%) aged ≥ 12 to < 18 years. The majority of patients were white(51.4%) and female (59.5%). Patients were either WHO FC I (25.0%), FC II (56.1%), or FC III(18.9%).

Idiopathic PAH was the most common aetiology in the study population (48.0%), followed by PAHassociated with post-operative congenital heart disease (28.4%), PAH with co-incidental congenitalheart disease (17.6%), heritable PAH (4.1%) and PAH associated with connective tissue disease(2.0%). Co-incidental CHD only included typically small coincidental defects such as pre-tricuspid,post-tricuspid shunts, atrial septal defect, ventricular septal defect, patent ductus arteriosus, noneconsidered causative of the degree of PAH.

The mean treatment duration in the randomised study was 183.4 weeks in the macitentan arm and130.6 weeks in the SoC arm.

Fewer events for the key secondary endpoint of CEC-confirmed disease progression were observed inthe macitentan arm (21 events/73 patients, 29%) versus the SoC arm (24 events/75 patients, 32%),absolute risk reduction of 3%. The hazard ratio was 0.828 (95% CI 0.460; 1.492; 2-sided stratifiedp-value = 0.567). The numerical trend towards benefit was mainly driven by the clinical worsening of

PAH.

Other secondary efficacy analyses

The same number of events for first-confirmed hospitalisation for PAH were observed in both groups(macitentan 11 vs. SoC 11; adjusted HR=0.912, 95% CI= [0.393; 2.118]). In terms of the time to

CEC-confirmed death due to PAH and death from all causes, a total of 7 deaths (6 of which were dueto PAH as per CEC) were observed in the macitentan arm compared to 6 deaths (4 of which were dueto PAH as per CEC) in the SoC arm.

There was a numerically higher proportion of patients at WHO FC I or II reported at Week 12 in themacitentan arm compared with the SoC arm (88.7% in macitentan arm versus 81.7% in SoC arm) andat Week 24 (90.0% in macitentan arm versus 82.5% in SoC arm).

Macitentan treatment tended to reduce the percent of baseline NT-proBNP (pmol/L) at Week 12compared with the SoC arm (geometric mean ratio: 0.72; 95% CI: 0.49 to 1.05) but the results werenot statistically significant (2-sided p-value of 0.086). The non-significant trend was less pronouncedat Week 24 (geometric mean ratio: 0.97;95% CI: 0.66 to 1.43;2-sided p-value of 0.884).

Efficacy results from patients aged ≥ 2 years to less than 18 years were similar to those of adultpatients.

Paediatric population (aged ≥ 1 month to less than 2 years)

An additional 11 patients, aged ≥ 1 month to less than 2 years old were enroled to receive macitentanwithout randomisation, 9 patients from the open-label arm of the TOMORROW study and 2 Japanesepatients from the PAH3001 study. PAH3001 was a multi-centre, open-label, single-arm, Phase 3 studyin Japanese paediatric participants (between ≥ 3 months and < 15 years of age) with PAH, conductedto assess the pharmacokinetics and efficacy of macitentan.

At baseline, 6 patients from the TOMORROW study were on PDE5i therapy. At enrolment, the agerange of the patients ranged from 1.2 years-1.9 years. Patients were either WHO FC II (4) or FC I (5).

PAH associated with congenital heart disease was the most common aetiology (5 patients), followedby idiopathic PAH (4 patients). The initially administered daily dose was 2.5 mg macitentan until thepatients reached the 2 years of age. After a median follow-up of 37.3 weeks, none of the patients hadexperienced a CEC-confirmed disease progression event, a CEC-confirmed hospitalisation for PAH, a

CEC-confirmed death due to PAH, or an event of death from all causes. NT-proBNP was reduced by42.9% (n=6) at Week 12, 53.2% (n=5) at Week 24 and 26.1% (n=6) at Week 36.

At baseline, 1 Japanese patient from the PAH3001 study was on PDE5i therapy. Both Japanesepatients were male and their ages at enrolment were 21 months and 22 months. Both patients were in

Panama FC I and II and the leading aetiology was post-operative PAH. At Week 24, a reduction inbaseline NT-proBNP levels of -3.894 pmol/L and -16.402 pmol/L was observed.

Exposure-matching to adult patients was not established in this age group (see sections 4.2 and 5.2).

The pharmacokinetics of macitentan and its active metabolite have mainly been documented inhealthy adult subjects. Exposure to macitentan in adult patients with PAH was approximately 1.2-foldgreater than in healthy subjects. The exposure to the active metabolite in patients, which isapproximately 5-fold less potent than macitentan, was approximately 1.3-fold higher than in healthysubjects. The pharmacokinetics of macitentan in PAH patients were not influenced by the severity ofthe disease.

After repeated administration, the pharmacokinetics of macitentan are dose-proportional up to andincluding 30 mg.

Maximum plasma concentrations of macitentan are achieved about 8-9 hours after administration forfilm-coated tablets and dispersible tablets. Thereafter, plasma concentrations of macitentan and itsactive metabolite decrease slowly, with an apparent elimination half-life of approximately 16 hoursand 48 hours, respectively.

In healthy adult subjects, the exposure to macitentan and its active metabolite is unchanged in thepresence of food and, therefore, macitentan may be taken with or without food.

Macitentan and its active metabolite are highly bound to plasma proteins (> 99%), primarily toalbumin and to a lesser extent to alpha1-acid glycoprotein. Macitentan and its active metabolite

ACT-132577 are well distributed into tissues as indicated by an apparent volume of distribution(Vss/F) of approximately 50 L and 40 L for macitentan and ACT-132577, respectively.

Macitentan has four primary metabolic pathways. Oxidative depropylation of the sulfamide yields apharmacologically active metabolite. This reaction is dependent on the cytochrome P450 system,mainly CYP3A4 (approximately 99%) with minor contributions of CYP2C8, CYP2C9 and CYP2C19.

The active metabolite circulates in human plasma and may contribute to the pharmacological effect.

Other metabolic pathways yield products without pharmacological activity. For these pathways,

CYP2C9 plays a predominant role with minor contributions from CYP2C8, CYP2C19 and CYP3A4.

Macitentan is only excreted after extensive metabolism. The major excretion route is via urine,accounting for about 50% of the dose.

Comparison between film-coated tablet and dispersible tablet formulations

Bioequivalence of macitentan 10 mg was established between the film-coated tablet and 4 x 2.5 mgdispersible tablets in a study with 28 healthy subjects.

There is no clinically relevant effect of sex or ethnic origin on the pharmacokinetics of macitentan andits active metabolite.

Exposure to macitentan and its active metabolite was increased by 1.3- and 1.6-fold, respectively, inadult patients with severe renal impairment. This increase is not considered clinically relevant (seesections 4.2 and 4.4).

Exposure to macitentan was decreased by 21%, 34%, and 6% and, for the active metabolite by 20%,25%, and 25% in adult subjects with mild, moderate or severe hepatic impairment, respectively. Thisdecrease is not considered clinically relevant (see sections 4.2 and 4.4).

Paediatric population (aged ≥ 1 month to less than 18 years)

Pharmacokinetics of macitentan and its active metabolite aprocitentan were characterised in47 paediatric patients who were ≥ 2 years and in 11 patients who were ≥ 1 month to less than 2 yearsold.

Weight-based dose regimens of macitentan resulted in observed/simulated exposures in paediatricpatients aged 2 years to less than 18 years that were comparable to exposures observed in adult PAHpatients and healthy subjects who received 10 mg once daily.

Exposures of macitentan comparable to that of adult PAH patients receiving 10 mg once daily werenot achieved for the age group of ≥ 1 month to less than 2 years old (see section 4.2).

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 39weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding isconsidered not relevant for humans.

Increased liver weight and hepatocellular hypertrophy were observed in mice, rats and dogs aftertreatment with macitentan. These changes were largely reversible and considered non-adverseadaptations of the liver to increased metabolic demand.

Macitentan induced minimal to slight mucosal hyperplasia and inflammatory infiltration in thesubmucosa of the nasal cavity in the mouse carcinogenicity study at all doses. No nasal cavity findingswere noted in the 3-month mouse toxicity study or in rat and dog studies.

Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays. Macitentan was notphototoxic in vivo after single dose at exposures of up to 24-fold the human exposure.

Carcinogenicity studies of 2 years’ duration did not reveal a carcinogenic potential at exposures18-fold and 116-fold the human exposure in rats and mice, respectively.

Testicular tubular dilatation was observed in chronic toxicity studies with male rats and dogs withsafety margins of 11.6 and 5.8, respectively. Tubular dilatation was fully reversible. After 2 years oftreatment, testicular tubular atrophy was seen in rats at 4-fold the human exposure.

Hypospermatogenesis was observed in the life-long carcinogenicity study in rats and in therepeat-dose toxicity studies in dogs at exposures that provide safety margins of 9.7 in rats and 23 indogs. The safety margins for fertility were 18 for male and 44 for female rats. No testicular findingswere noted in mice after treatment up to 2 years.

Macitentan was teratogenic in rabbits and rats at all doses tested. In both species there werecardiovascular and mandibular arch fusion abnormalities.

Administration of macitentan to female rats from late pregnancy through lactation at maternalexposures 5-fold the human exposure, caused reduced pup survival and impairment of thereproductive capability of the offspring, which was exposed to macitentan during late intrauterine lifeand via the milk during the suckling period.

Treatment of juvenile rats from postnatal Day 4 to Day 114 caused reduced body weight gain leadingto secondary effects on development (slight delay of descensus testis, reversible reduction oflong-bone length, prolonged estrous cycle). Slightly increased pre- and post-implantation loss,decreased mean number of pups, and decreased testis and epididymis weights, were observed atexposures 7-fold the human exposure. Testicular tubular atrophy, and minimal effects on reproductivevariables and sperm morphology were recorded at exposures 3.8-fold the human exposure.

Mannitol (E421)

Isomalt (E953)

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Not applicable.

2 years.

Store in original package to protect from moisture.

This medicinal product does not require any special temperature storage conditions.

30 x 1 dispersible tablets in Alu/Alu perforated unit dose blisters consisting of an aluminium cold formfilm with integrated desiccant and an aluminium push through lidding foil.

The oral suspension must be prepared by adding the dispersible tablet(s) to a little room temperatureliquid on a spoon or in a small glass to make a liquid medicine. When the tablet has fully dispersed,give the resulting liquid to the patient (see section 4.2).

Hands must be thoroughly washed and dried before and after preparation of the medicine.

Janssen-Cilag International NV

Turnhoutseweg 30

B 2340 Beerse

Belgium

EU/1/13/893/004

Date of first authorisation: 20 December 2013

Date of latest renewal: 23 August 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.