4.1. Therapeutic indications

Adults

Opsumit, as monotherapy or in combination, is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III (see section 5.1).

Paediatric population

Opsumit, as monotherapy or in combination, is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in paediatric patients aged less than 18 years and bodyweight ≥40 kg with WHO Functional Class (FC) II to III (see section 5.1).

4.2. Posology and method of administration

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

Posology

Adults and paediatric patients aged less than 18 years of age weighing at least 40 kg

The recommended dose is 10 mg once daily. Opsumit should be taken every day at about the same time.

If the patient misses a dose of Opsumit, the patient should be told to take it as soon as possible and then take the next dose at the regularly scheduled time. The patient should be told not to take two doses at the same time if a dose has been missed.

The 10 mg film-coated tablets are only recommended in paediatric patients weighing at least 40 kg. For paediatric patients weighing less than 40 kg, a lower strength of dispersible tablets of 2.5 mg is available. Please refer to the Opsumit dispersible tablets Summary of Product Characteristics.

Special populations

Elderly

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

Hepatic impairment

Based on pharmacokinetic (PK) data, no dose adjustment is required in patients with mild, moderate or severe hepatic impairment (see sections 4.4 and 5.2). However, there is no clinical experience with the use of macitentan in PAH patients with moderate or severe hepatic impairment. Opsumit must not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the upper limit of normal (>3 × ULN); see sections 4.3 and 4.4).

Renal impairment

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

Paediatric population

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 a posology can be made.

Method of administration

The film-coated tablets are not breakable and are to be swallowed whole, with water. They may be taken with or without food.

4.3. Contraindications

• Hypersensitivity to the active substance, soya 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 and 4.6).

• 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 alanine aminotransferases (ALT) >3 × ULN) (see sections 4.2 and 4.4).

4.4. Special warnings and precautions for use

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

Liver function

Elevations of liver aminotransferases (AST, ALT) have been associated with PAH and with endothelin receptor antagonists (ERAs). Opsumit is not to be initiated in patients with severe hepatic impairment or elevated aminotransferases (>3 × ULN) (see sections 4.2 and 4.3) and is not recommended in patients 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 is recommended. If sustained, unexplained, clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or by clinical symptoms of liver injury (e.g., jaundice), Opsumit treatment should be discontinued.

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

Haemoglobin concentration

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

Pulmonary veno-occlusive disease

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

Use in women of childbearing potential

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

Concomitant use with strong CYP3A4 inducers

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

Concomitant use with strong CYP3A4 inhibitors

Caution should be exercised when macitentan is administered concomitantly with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) (see section 4.5).

Concomitant use with moderate dual or combined CYP3A4 and CYP2C9 inhibitors

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

Renal impairment

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

Excipients with known effects

Opsumit contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Opsumit contains soya bean lecithin. If a patient is hypersensitive to soya, Opsumit must not be used (see section 4.3).

Other excipients

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

4.5. Interaction with other medicinal products and other forms of interaction

In vitro studies

The cytochrome P450 CYP3A4 is the main enzyme involved in the metabolism of macitentan and in the 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 clinically relevant inhibitory or inducing effects on cytochrome P450 enzymes.

Macitentan and its active metabolite are not inhibitors of hepatic or renal uptake transporters at clinically relevant concentrations, including the organic anion transporting polypeptides (OATP1B1 and 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 clinically relevant concentrations, including the multi-drug resistance protein (P-gp, MDR-1) and multidrug and toxin 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 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

Strong CYP3A4 inducers

Concomitant treatment with rifampicin 600 mg daily, a potent inducer of CYP3A4, reduced the steady-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 rifampicin should be considered. The combination of macitentan with strong CYP3A4 inducers should be avoided (see section 4.4).

Ketoconazole

In the presence of ketoconazole 400 mg once daily, a strong CYP3A4 inhibitor, exposure to macitentan increased approximately 2-fold. The predicted increase was approximately 3-fold in the presence of ketoconazole 200 mg twice daily using physiologically based pharmacokinetic (PBPK) modelling. The uncertainties of such modelling should be considered. Exposure to the active metabolite of macitentan was reduced by 26%. Caution should be exercised when macitentan is administered 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. The uncertainties of such modelling should be considered. Caution should be exercised when macitentan is administered concomitantly with moderate dual inhibitors of CYP3A4 and CYP2C9 (e.g., fluconazole and amiodarone) (see section 4.4).

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

Warfarin

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. The pharmacodynamic effect of warfarin on International Normalised Ratio (INR) was not affected by macitentan. The pharmacokinetics of macitentan and its active metabolite were not affected by warfarin.

Sildenafil

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

Cyclosporine A

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

Hormonal contraceptives

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 (riociguat 1 mg; rosuvastatin 10 mg).

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy, and lactation

Use in women of childbearing potential/Contraception in males and females

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

Pregnancy

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

Breastfeeding

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

Male fertility

The development of testicular tubular atrophy in male animals was observed after treatment with macitentan (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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile.

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

Tabulated list of adverse reactions

The safety of macitentan has been evaluated in a long-term placebo-controlled trial of 742 adult and adolescent patients with symptomatic PAH (SERAPHIN study). The mean treatment duration was 103.9 weeks in the macitentan 10 mg group, and 85.3 weeks in the placebo group. Adverse reactions associated with macitentan obtained from this clinical study are tabulated below. Post-marketing adverse 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 be estimated 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 disorders

Very common

Anaemia, haemoglobin 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

Hypotension,2 flushing

Respiratory, thoracic and mediastinal disorders

Common

Nasal congestion1

Hepatobiliary disorders

Common

Aminotransferase elevations4

Reproductive system and breast disorders

Common

Increased uterine bleeding8

General disorders and administration site conditions

Very common

Oedema, fluid retention3

1 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 exposure in females.

Description of selected adverse reactions

2 Hypotension has been associated with the use of ERAs including macitentan. In SERAPHIN, a long-term double-blind study in patients with PAH, hypotension was reported for 7.0% and 4.4% of patients on macitentan 10 mg and placebo, respectively. This corresponded to 3.5 events / 100 patient-years on macitentan 10 mg compared to 2.7 events / 100 patient-years on placebo.

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 the macitentan 10 mg and placebo treatment groups was 21.9% and 20.5%, respectively. In a double-blind study in adult patients with idiopathic pulmonary fibrosis, the incidence of peripheral oedema AEs in the macitentan and placebo treatment groups was 11.8% and 6.8%, respectively. In two double-blind clinical studies in adult patients with digital ulcers associated with systemic sclerosis, the incidences of peripheral 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 abnormalities

4 Liver aminotransferases

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

5 Haemoglobin

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

6 White blood cells

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

7 Platelets

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

Long-term safety

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

Long-term follow-up of these 550 patients for a median exposure of 3.3 years and a maximum exposure 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 to 17.9 years). The median duration of treatment in the randomised study was 168.4 weeks (range 12.9 weeks to 312.4 weeks) in the Opsumit arm.

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

An additional 5 Japanese patients (aged ≥2 years to less than 18 years) were treated with macitentan in the open-label Phase 3 study PAH3001. The median age at enrolment was 9 years (range 2 years to 13 years). The median duration of macitentan treatment in the study was 51.1 weeks (range 50.1 weeks to 52.6 weeks). Overall, the safety profile in this paediatric population was consistent with that observed in the TOMORROW study.

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 Opsumit without randomisation, 9 patients from the open-label arm of the TOMORROW study and 2 Japanese patients from the PAH3001 study. At enrolment, the age range of the patients from the TOMORROW study was 1.2 years to 1.9 years and the median duration of treatment was 37.1 weeks (range 7.0 to 72.9 weeks). At enrolment, the ages of the 2 patients from PAH3001 were 21 months and 22 months and the duration of treatment was 52.7 weeks and 51.6 weeks, respectively.

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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