Consumer medicine information

Opsumit

Macitentan

BRAND INFORMATION

Brand name

Opsumit

Active ingredient

Macitentan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Opsumit.

What is in this leaflet

This leaflet answers some common questions about OPSUMIT.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

If you have any concerns about using this medicine, speak to your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What OPSUMIT is used for

OPSUMIT tablets contain macitentan which belongs to the class of medicines called "endothelin receptor antagonists".

OPSUMIT is used for the treatment of pulmonary arterial hypertension (PAH), it can be used on its own or with other drugs to treat PAH. PAH is high blood pressure in the blood vessels (the pulmonary arteries) that carry blood from the heart to the lungs. In people with PAH, these arteries get narrower, so the heart has to work harder to pump blood through them. This causes people to feel tired, dizzy, and short of breath.

OPSUMIT widens the pulmonary arteries, making it easier for the heart to pump blood through them. This lowers the blood pressure and relieves the symptoms and improves the course of the disease.

Your doctor however, may prescribe OPSUMIT for another purpose.

Ask your doctor if you have any questions about why it has been prescribed for you.

Before you take OPSUMIT

When you must not take it

DO NOT take OPSUMIT if you are pregnant or if you are planning to become pregnant, or if you could become pregnant because you are not using reliable birth control (contraception). Talk to you doctor about what birth control methods are reliable whilst taking OPSUMIT.

Do not take OPSUMIT if you have ever had an allergic reaction to macitentan, soya or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following:

  • wheezing, swelling of the lips/mouth, difficulty in breathing, hay fever, lumpy rash (hives) or fainting.

Do not take OPSUMIT if you have liver disease or if you have very high levels of liver enzymes in your blood.

Talk to you doctor, who will decide if this medicine is suitable for you.

Do not use OPSUMIT after the expiry date [EXP.] printed on the pack. If you use it after the expiry date has passed, it may not work as well.

Do not use OPSUMIT if the packaging is torn or shows signs of tampering.

If you're not sure whether you should be using OPSUMIT, talk to your doctor.

The safety and efficacy of OPSUMIT has not been proven in patients under 12 years of age.

Before you start to take it

You must tell your doctor if:

  • you are allergic to foods, dyes, preservatives or any other medicines,
  • you have an intolerance to lactose or any other sugars. OPSUMIT contains small amounts of a sugar called lactose,
  • you are pregnant, trying or become pregnant,
  • you are breast-feeding,
  • you have liver problems,
  • you have kidney problems,
  • you have low blood pressure,
  • you have anaemia or low red blood cells.

Blood Tests

Your doctor will also order some blood tests before you start treatment with OPSUMIT and also during treatment with OPSUMIT, this is to test:

  • whether you have anaemia (a reduced number of red blood cells)
  • whether your liver is working properly.

Signs that your liver may not be working properly include:

  • nausea (urge to vomit)
  • vomiting
  • fever (high temperature)
  • pain in your stomach (abdomen)
  • jaundice (yellowing of your skin or the whites of your eyes)
  • dark-coloured urine
  • itching of your skin
  • lethargy or fatigue (unusual tiredness or exhaustion)
  • flu-like syndrome (joint and muscle pain with fever)

If you notice any of these signs, tell your doctor immediately.

Pregnancy and Breast-feeding

DO NOT take OPSUMIT if you or your partner are pregnant or planning to become pregnant as it may harm unborn babies conceived before, during or soon after treatment.

You must not become pregnant for at least 3 months after stopping OPSUMIT.

If you are a woman who could become pregnant, your doctor will ask you to take a pregnancy test before you take OPSUMIT and regularly (once a month) while you are taking OPSUMIT.

If you are a male you should avoid exposing your partner to your semen by use of appropriate contraception.

If it's possible you could become pregnant, use at least two reliable forms of birth control (contraception) while you're taking OPSUMIT. You must continue to use contraception for at least 3 months after stopping OPSUMIT. Talk to your doctor about this.

If you do become pregnant, talk to your doctor immediately.

DO NOT breast feed while you are taking OPSUMIT. You are advised to stop breastfeeding if OPSUMIT is prescribed for you, because it is not known whether this medicine passes into human breast milk.

Male fertility - the potential risk for humans is unknown. Talk to your doctor if you have any questions or concerns about this.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

You must tell you doctor if you are taking:

  • rifampicin, clarithromycin, (used to treat infections)
  • phenytoin (a medicine used to treat seizures)
  • carbamazepine (a medicine used to treat depression and epilepsy)
  • St. John's Wort (a herbal preparation used to treat depression)
  • ritonavir, saquinavir (used to treat HIV infections)
  • ketoconazole (except shampoo), itraconazole, voriconazole (medicines used to treat fungal infections)

Some medicines may affect the way other medicines work. Your doctor or pharmacist will be able to tell you what to do when using OPSUMIT with other medicines.

How to take OPSUMIT

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

How much to take

The recommended dose of OPSUMIT for adults and children over 12 years of age and weighing more than 40 kg is one 10 mg tablet, once a day.

Swallow the whole tablet, with a glass of water, do not chew or break the tablet.

You can take OPSUMIT with or without food.

How to take it

Use OPSUMIT for as long as your doctor advises you to. OPSUMIT is generally used over a prolonged period of time, possibly years. It should not be stopped suddenly.

If you forget to take it

If you forget to take OPSUMIT, take a dose as soon as you remember, then continue to take your tablets at the usual times. Do not take a double dose to make up for a forgotten tablet.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre or go to accident and emergency at you nearest hospital if you think you or anyone else may have taken too much OPSUMIT. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention or advice on management of overdose.

Poison Information Centre telephone numbers:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766

While you are using OPSUMIT

Things you must do

Tell your doctor or pharmacist that you are taking OPSUMIT if you are about to start on any new medicines.

Tell your doctor if you become pregnant or are trying to become pregnant.

Tell your doctor if, for any reason, you have not used your medicine exactly as prescribed.

Things you must not do

OPSUMIT is a treatment that you will need to keep on taking to control your PAH.

Do not stop taking OPSUMIT unless you have agreed this with your doctor.

If you have any further questions on the use of OPSUMIT, ask your doctor or pharmacist.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use OPSUMIT to treat any other complaints unless your doctor says to.

Things to be careful of

As with many other medicines, OPSUMIT may cause headaches in some people.

Be careful driving or operating machinery until you know how OPSUMIT affects you. If you are affected, do not drive or operate machinery.

Side effects

Check with your doctor as soon as possible if you have any problems while taking OPSUMIT, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like all medicines, OPSUMIT can cause side effects in some people.

Tell your doctor at once if you experience any of the following while you are receiving OPSUMIT:

Very common side effects

  • Anaemia (low number of red blood cells) or haemoglobin decreases
  • Headache
  • Bronchitis (inflammation of the airways)
  • Nasopharyngitis (inflammation of the throat & nasal passages)
  • Oedema and peripheral oedema/fluid retention (swelling especially in the ankles and feet)
  • Upper respiratory tract infection

Common side effects

  • Diarrhoea
  • Abdominal pain
  • Gastroenteritis (inflammation of stomach and gut)
  • Irritable bowel syndrome (stomach pain and bloating with diarrhoea or constipation)
  • Urinary tract infection (bladder infection)
  • Fever
  • Tonsillitis
  • Pharyngitis (inflammation of the throat)
  • Influenza (flu)
  • Viral infection of nose, throat or chest
  • Sinusitis (sinus infection)
  • Lower respiratory tract infection
  • Inflammation of respiratory tract
  • Itchy, runny or blocked nose
  • Increased sensitivity of the airways in the lungs, causing narrowing and difficulty breathing
  • Infection of the windpipe
  • Hypotension (low blood pressure)
  • Pruritus (severe itching of the skin)
  • Eczema (itchy skin rash)
  • Thrombocytopenia (low number of platelets (cells that help blood to clot))
  • Haematocrit decreased (decreased proportion of red blood cells in the blood)
  • Hypokalemia (low level of potassium in the blood)
  • Hyperkalaemia (high level of potassium in the blood)
  • Increased level of urea in the blood
  • Difficulty sleeping
  • Ulcer or sore on the skin
  • Conjunctivitis (inflammation of the eye)
  • Haemorrhoids
  • Gallstones
  • Problem with the immune system that causes a build up of scar tissue in the skin and internal organs (systemic scleroderma)
  • Inflamed tissue (cartilage) in the rib cage
  • Bleeding between monthly menstrual periods
  • Long or heavy menstrual periods
  • Cyst in the ovary
  • Enlarged breasts in men
  • Flushing
  • Joint pain
  • Muscle pain
  • Depression

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

This is not a complete list of all possible side-effects. Others may occur in some people and there may be some side-effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor if you don't understand anything in this list.

Storing OPSUMIT

Storage

Keep this medicine where young children cannot reach it.

A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Do not leave them in the car or on window sills.

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.

Do not store above 30°C.

Disposal

Medicines should not be disposed of in wastewater or household waste.

Ask your pharmacist how to dispose of medicines you no longer require. These measures will help to protect the environment.

Product description

What it looks like

OPSUMIT 10 mg tablets are white to off white, biconvex, round, film-coated tablets with "10" on both sides.

Pack size

OPSUMIT is supplied as 10 mg film-coated tablets in blister packs of, 9 or 30 tablets.

Ingredients

Active ingredient: Each tablet of OPSUMIT contains 10 mg of macitentan.

Inactive ingredients:

  • lactose 38.86mg
  • microcrystalline cellulose
  • povidone
  • sodium starch glycolate type A
  • magnesium stearate
  • polysorbate 80
  • polyvinyl alcohol
  • titanium dioxide
  • purified talc
  • soya lecithin
  • xanthan gum.

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Road
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

NZ Office: Auckland New Zealand
Telephone: 0800 800 806

This leaflet was prepared in July 2020.

OPSUMIT 10 mg tablets packs:

  • blister packs of 9 tablets AUST R 205624
  • blister packs of 30 tablets AUST R 205624

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Opsumit

Active ingredient

Macitentan

Schedule

S4

 

1 Name of Medicine

Opsumit (macitentan).

6.7 Physicochemical Properties

Active: macitentan.
Opsumit is the brand name for macitentan and is a dual ETA and ETB 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.
The molecular formula: C19H20Br2N6O4S.
Relative molecular mass: 588.3 g/mol, the molecule is achiral.

Chemical structure.


CAS number.

441798-33-0.
Macitentan is a white to off white crystalline powder that is insoluble in water and slightly soluble in ethanol (approx 2 mg/mL). In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive. The melting temperature of macitentan is 135°C, Partition coefficient (1-octanol/ aqueous phosphate buffer, pH 7.4): log D = 2.9 and ionization constant pKa is 6.2.

2 Qualitative and Quantitative Composition

Opsumit is available as a 10 mg film-coated tablet for once daily oral administration. The tablets include the following inactive ingredients: lactose, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycollate type A.
See Section 6.1 List of Excipients.

3 Pharmaceutical Form

The tablets are film-coated with a coating material containing polyvinyl alcohol, lecithin, purified talc, titanium dioxide, and xanthan gum. Each white, round, biconvex film-coated tablet, debossed with "10" on both sides.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of effects such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as pulmonary arterial hypertension (PAH), the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage.
Macitentan is an orally active, dual ETA and ETB receptor antagonist that prevents the binding of ET-1 to its receptors. Macitentan displays high affinity for and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells and has physicochemical properties favouring penetration into lung tissue, particularly in disease conditions.
In animal models of pulmonary hypertension, macitentan selectively decreased mean pulmonary arterial pressure without affecting systemic blood pressure, prevented pulmonary arterial hypertrophy and right ventricular remodeling, and significantly increased survival.

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.

Clinical trials.

Efficacy in patients with pulmonary arterial hypertension.

A multicentre, 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 were randomised to three treatment groups (placebo [N = 250], 3 mg [N = 250] or 10 mg [N = 242] of macitentan once daily), to assess the long-term effect on morbidity or mortality. At baseline, the majority of enrolled patients (64%) were treated with a stable dose of specific therapy for PAH, either oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostanoids (6%). The primary study endpoint was the time to first occurrence of a morbidity or mortality event, up to end of treatment (EOT), defined as death, or atrial septostomy, or lung transplantation, or initiation of intravenous (i.v.) or subcutaneous (s.c.) prostanoids, or other worsening of PAH. Other worsening of PAH was defined as the presence of all of the three following components: a sustained decrease in 6 minute walk distance (6MWD) of at least 15% from baseline; worsening of PAH symptoms (worsening of WHO Functional Class [FC] or right heart failure); and need for new treatment for PAH. All events were confirmed by an independent adjudication committee, blinded to treatment allocation.
The median treatment duration was 101, 116, and 118 weeks in the placebo, macitentan 3 mg, and 10 mg group, respectively, up to a maximum of 188 weeks on macitentan.
Efficacy was evaluated up to the end of double blind treatment (EOT). The EOT either coincided with end of study (EOS) for patients who completed the study as scheduled or occurred earlier in case of premature discontinuation of study drug. For those patients who stopped treatment prior to EOS, PAH therapy, including macitentan, may have been initiated. All patients were followed up to EOS for vital status. The ascertainment rate for vital status at the EOS was greater than 95%.
The mean age of all patients was 46 years (range 12-85 years of age) with the majority of subjects being Caucasian (55%) and female (77%). Approximately 52%, 46%, and 2% of patients were in WHO FC II, III, and IV, respectively. Patients with WHO Functional Class I were excluded from the study.
Idiopathic or heritable PAH was the most common aetiology in the study population (57%), followed by PAH due to connective tissue disorders (31%), PAH associated with congenital heart disease with shunts (8%), and PAH associated with other aetiologies (drugs and toxins [3%] and HIV [1%]).

Outcome endpoints.

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 (Figure 1 and Table 6). 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). The treatment effect was established early and sustained for a median duration of 2 years.
Subgroup analyses were performed to examine their influence on outcome as shown in Figure 2. 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.
The SERAPHIN study was not powered to assess the effect on mortality. Treatment with Opsumit 10 mg resulted in a statistically nonsignificant 36% relative risk reduction (HR 0.64, 97.5% CI: 0.29-1.42; logrank p = 0.2037) in the occurrence of death of all causes 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 (HR 0.77; 97.5% CI: 0.46 to 1.28; logrank p = 0.2509).
The risk of PAH related death or hospitalisation for PAH up to the end of double blind treatment was reduced by 50% in patients receiving macitentan 10 mg (50 events) (HR 0.50; 97.5% CI: 0.34-0.75; logrank p < 0.0001) compared to placebo (84 events) (Figure 3 and Table 7).

Symptomatic endpoints.

Exercise capacity was evaluated as a secondary endpoint. Treatment with macitentan 10 mg at Month 6 resulted in a placebo corrected mean increase in Six Minute Walk Distance (6MWD) of 22 metres (97.5% CI: 3-41). Evaluation of 6MWD by functional class resulted in a placebo corrected mean increase from baseline to Month 6 in FC III/IV patients of 37 metres (97.5% CI: 5-69) and in FC I/II of 12 metres (97.5% CI: -8-33). The increase in 6MWD achieved with macitentan was maintained for the duration of the study.
Treatment with macitentan 10 mg led to a 74% higher chance of WHO FC improvement relative to placebo (risk ratio 1.74; 97.5% CI: 1.10-2.74). Treatment with macitentan 10 mg led to an improvement of at least one WHO FC at Month 6 in 22% of patients compared to 13% of patients treated with placebo.
Macitentan 10 mg improved quality of life assessed by the SF-36 questionnaire.

Haemodynamic endpoints.

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 median reduction of 36.5% (CI: 21.7-49.2%) in pulmonary vascular resistance and an increase of 0.58 L/min/m2 (CI: 0.28-0.93 L/min/m2) in cardiac index compared to placebo.

5.2 Pharmacokinetic Properties

The pharmacokinetics of macitentan and its active metabolite have mainly been documented in healthy subjects. Exposure to macitentan in patients with PAH was approximately 1.2-fold greater than in healthy subjects. The exposure to the active metabolite in patients, which is approximately 5-fold less potent than macitentan, was approximately 1.3-fold higher than in healthy subjects. The pharmacokinetics of macitentan in PAH patients were not influenced by the severity of the disease.
After repeated administration, the pharmacokinetics of macitentan are dose proportional up to and including 30 mg.

Absorption.

Maximum plasma concentrations of macitentan are achieved about 8 hours after administration. The absolute bioavailability after oral administration is not known. Thereafter, plasma concentrations of macitentan and its active metabolite decrease slowly, with an apparent elimination half-life of approximately 16 hours and 48 hours, respectively.
In healthy subjects, the exposure to macitentan and its active metabolite is unchanged in the presence of food and, therefore, macitentan may be taken with or without food.

Distribution.

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.

Macitentan has four primary metabolic pathways. The most important is oxidative depropylation of the sulfamide to yield a pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 system, mainly CYP3A4 (approximately 99%) with minor contributions from 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. Several members of the CYP2C family, namely CYP2C8, CYP2C9 and CYP2C19, as well as CYP3A4, are involved in the formation of these metabolites.

Excretion.

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

Special populations.

There is no clinically relevant effect of age, sex or ethnic origin on the pharmacokinetics of macitentan and its active metabolite.

Renal impairment.

Exposure to macitentan and its active metabolite was increased by 1.3 and 1.6-fold, respectively, in patients with severe renal impairment.

Hepatic impairment.

Exposure to macitentan was decreased by 21%, 34%, and 6% and for the active metabolite by 20%, 25%, and 25% in subjects with mild, moderate or severe hepatic impairment, respectively.

5.3 Preclinical Safety Data

Genotoxicity.

Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays.

Carcinogenicity.

Studies of 2 years duration did not reveal a carcinogenic potential at exposures 18-fold and 116-fold the human exposure in rats and mice, respectively.

4 Clinical Particulars

4.1 Therapeutic Indications

Opsumit, as monotherapy or in combination with approved PAH treatments (phosphodiesterase-5 inhibitors or inhaled prostanoids), is indicated for the treatment of:
idiopathic pulmonary arterial hypertension;
heritable pulmonary arterial hypertension;
pulmonary arterial hypertension associated with connective tissue disease;
pulmonary arterial hypertension associated with congenital heart disease with repaired shunts in patients with WHO Functional class II, III or IV symptoms.

4.3 Contraindications

Opsumit is contraindicated in:
Women who are or may become pregnant (see Boxed Warnings; see Section 4.6 Fertility, Pregnancy and Lactation).
Women of childbearing potential who are not using reliable contraception (see Section 4.6 Fertility, Pregnancy and Lactation). Women must not become pregnant for at least 3 months after stopping treatment with Opsumit.
Hypersensitivity to the active substance or to any of the excipients listed, see Section 6.1 List of Excipients.
Patients with severe hepatic impairment (with or without cirrhosis) (see Section 4.4 Special Warnings and Precautions for Use, Liver function).
Patients with baseline values of hepatic aminotransferases (aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT]) greater than 3 times the Upper Limit of Normal (ULN) (see Section 4.4 Special Warnings and Precautions for Use, Liver function).

4.4 Special Warnings and Precautions for Use

Macitentan has only been studied in a limited number of patients with WHO functional class IV symptoms.
Macitentan has only been studied in a limited number of patients with PAH due to HIV, drugs or toxins.
The efficacy and safety of macitentan when coadministered with epoprostenol has not been specifically studied in controlled clinical trials.

Liver function.

Hepatic enzyme elevations, and in some cases serious hepatic events, potentially related to therapy have been observed with endothelin receptor antagonists (ERAs).
The incidence of aminotransferase elevations (ALT/AST) > 3 x ULN was 3.4% on macitentan 10 mg and 4.5% on placebo in a double blind study in patients with PAH. The incidence of elevations in ALT > 3 x ULN were 3.4% on macitentan 10 mg and 1.6% on placebo (see Section 4.8 Adverse Effects (Undesirable Effects)). The incidence of ALT > 8 x ULN were 2.1% on macitentan 10 mg and 0.4% on placebo.
Opsumit is not to be initiated in patients with severe hepatic impairment or elevated aminotransferases (> 3 x ULN) (see Section 4.3 Contraindications) and is not recommended in patients with moderate hepatic impairment. Liver enzyme tests should be obtained prior to initiation of macitentan and monthly monitoring of aminotransferases during treatment with macitentan is recommended. Patients should be monitored for signs of hepatic injury.
If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin > 2 x ULN, or by clinical symptoms of hepatic injury (e.g. jaundice), macitentan treatment should be discontinued. Reinitiation of macitentan may be considered following the return of hepatic enzyme levels to within the normal range in patients who have not experienced clinical symptoms of hepatic injury and following the advice of a liver specialist.
Caution should be exercised when Opsumit is used concomitantly with medicinal products known to be associated with hepatic injury as the additive effects of Opsumit with these agents are not known.

Haematological changes.

Decreases in haemoglobin concentration and haematocrit have occurred following administration of other ERAs and were observed in clinical studies with Opsumit (see Section 4.8 Adverse Effects (Undesirable Effects)).
In placebo controlled studies, macitentan related decreases in haemoglobin concentration were not progressive, stabilised after the first 4-12 weeks of treatment and remained stable during chronic treatment. Cases of anaemia requiring blood cell transfusion have been reported with Opsumit and other ERAs. Initiation of Opsumit is not recommended in patients with clinically significant anaemia. It is recommended that haemoglobin concentrations be measured prior to initiation of treatment and tests repeated during treatment as clinically indicated.

Fluid retention.

Oedema or fluid retention has been observed with ERAs and may also be a clinical consequence of PAH. Opsumit 10 mg was not associated with increased incidences of treatment emergent oedema or fluid retention in a long-term placebo controlled trial (see Section 4.8 Adverse Effects (Undesirable Effects)).
If clinically significant fluid retention develops during therapy with Opsumit, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as underlying heart failure, and the possible need for specific treatment should be considered.

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 Opsumit is administered in patients with PAH, the possibility of pulmonary veno-occlusive disease should be considered. Discontinuation of Opsumit should be considered in patients with treatment related pulmonary veno-occlusive disease.

Use in 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 Opsumit in patients with severe renal impairment. Caution is recommended in this population. There is no experience with the use of Opsumit in patients undergoing dialysis, therefore Opsumit is not recommended in this population.

Use in patients with pre-existing hypotension.

Hypotension has been associated with the use of ERAs. Caution should be exercised when initiating macitentan in patients with pre-existing hypotension and blood pressure in such patients should be monitored closely.

Use in the elderly.

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. Limited data are available in those > 75 years of age, therefore caution is recommended.

Paediatric use.

The safety and efficacy of Opsumit in children below the age of 12 years have not yet been established. There is no data available on the effects of macitentan on growth and development in paediatric patients. There is limited clinical experience in paediatric patients aged 12 and above (see Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Laboratory abnormalities.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro studies.

The metabolism of macitentan to its active metabolite is catalysed by CYP3A4 and to a minor extent by CYP2C19.
Macitentan and its active metabolite do not have clinically relevant inhibitory or inducing effects on CYP enzymes.
Macitentan and its active metabolite are not substrates of the multidrug resistance protein (P-gp, MDR-1) or organic anion transporting polypeptides (OATP1B1 and OATP1B3).
Macitentan and its active metabolite are unlikely to inhibit hepatic or renal drug transporters at clinically relevant concentrations, including the multidrug resistance protein (P-gp, MDR-1), the multidrug and toxin extrusion transporters (MATE1 and MATE2-K), the organic anion transporters (OAT1 and OAT2), the organic cation transporters (OCT1 and OCT2), the bile salt export pump (BSEP), the sodium dependent cotransporting polypeptide (NTCP), and the organic anion transporting polypeptides (OATP1B1 and OATP1B3).

In vivo studies.

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 Normalized 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 t.i.d. 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.

Strong CYP3A4 inhibitors.

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. Exposure to the active metabolite of macitentan was reduced by 26%. Caution should be exercised when macitentan is administered concomitantly with strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, clarithromycin, ritonavir, and saquinavir).

HIV drugs.

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.

Cyclosporine A.

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

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 (e.g. rifampicin, St John's wort, carbamazepine, and phenytoin) should be avoided.

Hormonal contraceptives.

Macitentan does not affect the exposure to CYP3A4 substrates. In healthy subjects, macitentan 10 mg once daily did not affect the pharmacokinetics of a single dose of an oral contraceptive (norethisterone 1 mg and ethinylestradiol 35 microgram).

Breast cancer resistance protein (BCRP) substrate drugs.

Macitentan 10 mg once daily did not affect the pharmacokinetics of oral riociguat or rosuvastatin (riociguat 1 mg, rosuvastatin 10 mg).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Male fertility.

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. The clinical relevance of this finding cannot be excluded. Macitentan did not affect male or female fertility in rats at exposures ranging from approximately 18 to 44-fold the human exposure, respectively. In a 26 week study in male rats treated with macitentan, there was no effect on sperm count or motility but there was a dose dependent increase in the incidence of morphologically abnormal sperm at or above 7-fold the human exposure. No testicular findings were noted in mice after treatment up to 2 years.
Exploratory study results in healthy subjects with 12 weeks of treatment duration showed that 10 mg macitentan was associated with a 28% mean reduction in sperm concentration which is not considered clinically relevant. Changes in sperm morphology and motility were within the range of the variability of the measurements.
(Category X)
Due to a high mortality risk to both mother and foetus, pregnancy is considered contraindicated in PAH.
Teratogenicity is a class effect of endothelin receptor antagonists.
There are no data on the use of macitentan in pregnant women. Opsumit is contraindicated during pregnancy and in women of childbearing potential who are not using reliable contraception. If Opsumit is used during pregnancy, or if the patient becomes pregnant while taking Opsumit, advise the patient of the potential harm to the foetus.
Macitentan was teratogenic in rabbits and rats at all doses tested. In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. A no-effect level for teratogenicity has not been established. 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.

Use in women of childbearing potential.

In females of childbearing potential, pregnancy should be excluded before the start of treatment with macitentan and prevented thereafter by the use of two reliable methods of contraception. If necessary, patients should discuss with their doctor or gynaecologist which methods would be most suitable for them. Given the teratogenic nature of the drug, women should not become pregnant for 3 months after discontinuation of Opsumit. Monthly pregnancy tests during treatment with Opsumit are recommended to allow the early detection of pregnancy.
It is not known whether macitentan is present in semen. It is therefore not known whether there is the potential for foetal harm (teratogenicity) resulting from transfer of macitentan via semen.
It is not known whether Opsumit is excreted into human breast milk. In rats, Opsumit and its metabolites were excreted into milk during lactation. Breastfeeding is not recommended during treatment with Opsumit. A risk to newborns/infants cannot be excluded.

4.8 Adverse Effects (Undesirable Effects)

Experience from clinical studies.

The safety of macitentan has been evaluated in a long-term placebo controlled trial of 742 patients with symptomatic PAH. The mean treatment duration was 103.9 weeks in the macitentan 10 mg group, and 85.3 weeks in the placebo group. The majority of adverse events were mild to moderate in intensity. The most commonly reported adverse events were nasopharyngitis (14.0% vs 10.4%), headache (13.6% vs 8.8%) and anaemia (13.2% vs 3.2%) (Table 1).
Table 2 presents adverse reactions occurring in macitentan treated subjects at an incidence < 3% and with a placebo corrected difference ≥ 1% (during treatment and up to 28 days after treatment discontinuation). Adverse reactions are listed by system organ class and frequency category, using the convention: common (≥ 1/100 and < 1/10). Within each frequency group, adverse reactions are presented in order of decreasing seriousness.
Frequency determination does not account for other factors including varying study duration, pre-existing conditions, and baseline patient characteristics.
Oedema/fluid retention has been associated with the use of ERAs and is also a clinical manifestation of right heart failure and underlying PAH disease. In 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. This corresponded to 11.0 events/100 patient years on macitentan 10 mg compared to 12.5 events/100 patient years on placebo.

Postmarketing experience.

See Table 3.

Laboratory abnormalities.

Liver aminotransferases.

The incidence of elevated aminotransferases in the study of Opsumit in PAH is shown in Table 4 and 5.
In a double blind study in patients with PAH, discontinuations for hepatic adverse events were 3.3% in the Opsumit 10 mg group vs. 1.6% for placebo.

Haemoglobin.

In a double blind study in patients with PAH, macitentan 10 mg was associated with a mean decrease in haemoglobin versus placebo of 10 g/L. A decrease from baseline in haemoglobin concentration to below 100 g/L was reported in 8.7% of patients treated with macitentan 10 mg and 3.4% of placebo treated patients.

White blood cells.

In 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 x 109/L versus no change in placebo treated patients.

Platelets.

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

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at https://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Treatment with Opsumit should only be initiated and monitored by a physician experienced in the treatment of PAH.
Opsumit is to be taken orally at a dose of 10 mg once daily, with or without food. The film coated tablets are not breakable and are to be swallowed whole, with water. Doses higher than 10 mg daily have not been studied and are not recommended.

Dosage adjustment in elderly patients.

No dose adjustment is required in patients over the age of 65 years.

Dosage adjustment in patients with hepatic impairment.

Based on pharmacokinetic data, no dose adjustment is required in patients with mild or moderate hepatic impairment. There is no clinical experience with the use of Opsumit in PAH patients with moderate or severe hepatic impairment.
Opsumit is contraindicated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the Upper Limit of Normal (> 3 x ULN)); see Section 4.3 Contraindications.

Dosage adjustment in patients with 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 Opsumit in PAH patients with severe renal impairment. The use of Opsumit is not recommended in patients undergoing dialysis.

Dosage adjustment in paediatric population.

There is limited clinical experience in paediatric patients aged 12 and above therefore caution is advised; the recommended dose is 10 mg once daily in patients aged 12 and above and with body weight > 40 kg. The safety and efficacy of Opsumit in children below the age of 12 years have not yet been established.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. See Section 4.8 Adverse Effects (Undesirable Effects).

4.9 Overdose

Macitentan has been administered as a single dose of up to and including 600 mg to healthy subjects. Adverse events 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.
Contact the Poisons Information Centre on 13 11 26 for advice on management of overdose.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Lactose monohydrate, microcrystalline cellulose, sodium starch glycolate Type A, povidone, magnesium stearate, polysorbate 80.

Film coat.

Polyvinyl alcohol, titanium dioxide, talc, soya lecithin, xanthan gum.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store Opsumit below 30°C, protect from moisture.

6.5 Nature and Contents of Container

Blisters: PVC/PE/PVdC/Aluminium foil blisters in cartons containing 9 x 10 mg macitentan film-coated tablets, starter pack, AUST R 205624.
Blisters: PVC/PE/PVdC/Aluminium foil blisters in cartons containing 30 x 10 mg macitentan film-coated tablets, AUST R 205624.

6.6 Special Precautions for Disposal

No special precautions for disposal.

Summary Table of Changes