JERAYGO Film-coated tablet Ref.[111534] Active ingredients: Aprocitentan

Women of childbearing potential, pregnant and breast-feeding women

JERAYGO is contraindicated for use in women who are pregnant, breast-feeding and in women of childbearing potential who are not using reliable contraception (see sections 4.3 and 4.6).

Pregnancy tests are recommended before the start of treatment, monthly during treatment, and one month after stopping treatment to allow detection of pregnancy (see section 4.6).

Hepatotoxicity

Elevations of aminotransferases and hepatotoxicity are known effects of other endothelin receptor antagonists (ERAs). Elevations of transaminases have been reported infrequently in clinical trials of aprocitentan (see section 4.8).

JERAYGO must not be initiated in patients with severe hepatic impairment (see section 4.3) and is not recommended in patients with elevated aminotransferases (>3 × upper limit of normal [ULN]). Liver enzyme tests should be obtained prior to initiation of JERAYGO.

During treatment, monitoring of liver enzymes 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 hepatotoxicity, JERAYGO should be discontinued.

Fluid retention

Peripheral oedema and fluid retention are known effects of ERAs and were observed in clinical studies with aprocitentan (see section 4.8). After treatment initiation, patients should be monitored for signs of fluid retention such as oedema or weight gain. If clinically significant fluid retention develops, the patient should be evaluated to determine the cause and the need for additional supportive treatment, including additional diuretics or increase of dose of currently prescribed diuretic (as appropriate), before considering dose reduction or discontinuation of JERAYGO.

In patients treated with loop diuretics before starting therapy with JERAYGO, the loop diuretic should not be switched to a less effective diuretic at initiation.

Patients with underlying renal impairment (eGFR <60 mL/min/1.73 m²) or pre-existing heart failure taking JERAYGO may be at a higher risk of developing fluid retention, as may elderly patients (>65 years), patients with diabetes, or severely obese patients (body mass index [BMI] ≥40 kg/m²). When switching to 25 mg, the risk of increasing fluid retention, potentially aggravating heart failure or cardiovascular (CV) events, has to be taken into consideration in these patients.

Cardiovascular events

Aprocitentan has not been studied in patients with unstable or severe cardiac disease, such as uncontrolled symptomatic arrhythmia (including atrial fibrillation), heart failure New York Heart Association stage III–IV or stage II with relevant valve disease, with NT-proBNP plasma concentration ≥500 pg/mL, or with recent (within 6 months) unstable angina, myocardial infarction, transient ischemic attack or stroke. JERAYGO is not recommended in these patients.

Due to the general risk of CV events in patients with resistant hypertension and since aprocitentan can cause fluid retention, patients at high risk of developing congestive heart failure or other CV events should be monitored for signs and symptoms of fluid retention.

The benefit and risk of continuation or discontinuation of JERAYGO if patients experience CV events while on treatment should be assessed on an individual basis.

Haemoglobin decrease

Decreases in haemoglobin concentration and haematocrit have occurred following administration of ERAs and were observed in clinical studies with aprocitentan (see section 4.8). These decreases have been attributed to plasma volume expansion (haemodilution). In the clinical studies of aprocitentan, they stabilised after 4 weeks of treatment, remained stable during chronic treatment, and were reversible within 4 weeks after discontinuation.

Initiation of JERAYGO is not recommended in patients with severe anaemia (< 8 g/dL). If clinically indicated, haemoglobin concentrations should be measured prior to initiation of treatment and during treatment. If clinically relevant signs and symptoms related to haemoglobin decrease are observed, consider discontinuation of JERAYGO.

Renal impairment

Patients with eGFR below 60 mL/min/1.73 m² may have a higher risk of experiencing anaemia and oedema/fluid retention during treatment with JERAYGO. Therefore, it is recommended to monitor haemoglobin, and for signs of fluid retention or heart failure.

There is no clinical experience with the use of aprocitentan in patients with resistant hypertension and eGFR <15 mL/min/1.73 m² or in patients undergoing dialysis; therefore, JERAYGO is not recommended in these patients.

Patients ≥75 years of age

Patients ≥75 years of age may have a higher risk of experiencing anaemia, oedema/fluid retention, heart failure, and cerebrovascular events. It is recommended to monitor haemoglobin, and for signs of fluid retention or heart failure.

Excipients with known effect

Lactose monohydrate

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

Sodium

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

Effect of other medicinal products on the pharmacokinetics of aprocitentan

Based on its pharmacokinetic (PK) profile, aprocitentan exposure is not expected to be impacted by other medicinal products that are inhibitors or inducers of transporters and/or CYP enzymes.

Effect of aprocitentan on the pharmacokinetics of other medicinal products

CYP enzymes and BCRP substrates

In a clinical study conducted in healthy subjects, co-administration of once daily 50 mg aprocitentan with the sensitive CYP3A4 substrate midazolam did not affect the PK of midazolam, leading to the conclusion of the absence of interaction with CYP enzymes, with the exception of the potential induction of CYP2B6 and CYP1A2 enzymes described below.

In vitro studies are inconclusive regarding the potential of aprocitentan to induce CYP2B6 and CYP1A2. In vivo induction cannot be excluded. Caution is recommended when aprocitentan is co-administered with CYP1A2 substrates with a narrow therapeutic index (e.g., tizanidine).

In a clinical study conducted in healthy subjects receiving 25 mg aprocitentan and rosuvastatin, a BCRP substrate, once daily dosing of aprocitentan increased C_max of rosuvastatin by 40%; however, the total exposure to rosuvastatin expressed as AUC_0-∞ was unchanged. Therefore, BCRP substrates can be administered with aprocitentan.

Aprocitentan does not impact the PK of medicinal products for which PK is dependent on active transport, with the exception of OAT3 substrates described below.

OAT3 substrates

In vitro, aprocitentan is an OAT3 inhibitor. Therefore, aprocitentan may increase plasma concentrations of medicinal products for which excretion is dependent upon OAT3. Whether this would result in a clinically relevant effect on the PK of concomitantly administered substrates of OAT3 cannot be excluded as a dedicated interaction study has not been performed. Therefore, caution should be exercised when OAT3 substrates with a narrow therapeutic index (e.g., methotrexate) are given concomitantly.

Hormonal contraceptives

The potential interaction between aprocitentan and hormonal contraceptives has not been studied. Therefore, women using hormonal contraceptives should add a barrier method.

Use in women of childbearing potential/Contraception in females

JERAYGO is contraindicated for use in women of childbearing potential not using contraception.

Women of childbearing potential must be advised to use reliable methods of contraception during treatment and for one month after treatment discontinuation, as women should not become pregnant during this time. Since the potential interaction between aprocitentan and hormonal contraceptives has not been studied, women using hormonal contraceptives should add a barrier method.

Women of childbearing potential are recommended to perform a pregnancy test before the start of treatment, monthly during treatment, and one month after stopping treatment to allow for the early detection of pregnancy. If pregnancy is detected, JERAYGO must be discontinued (see sections 4.3 and 4.4).

A card addressed to the patient is included in the packaging. It contains information regarding the risk of harm to the unborn child, the need to use contraceptive measures and the recommendation for pregnancy testing.

Pregnancy

There are no or limited amount of data on the use of aprocitentan in pregnant women. Since studies in animals with other ERAs have shown reproductive toxicity, JERAYGO is contraindicated during pregnancy (see section 4.3).

Breast-feeding

It is unknown whether aprocitentan/metabolites are excreted in human milk. In rats, aprocitentan was excreted into milk during lactation.

A risk to the breastfed infant cannot be excluded. JERAYGO is contraindicated during breast-feeding (see section 4.3).

Fertility

An increased incidence of testicular tubular dilation, and, as a long-term consequence, of tubular degeneration/atrophy in male rats was observed after treatment with aprocitentan, similarly to other ERAs. However, such effects were only observed at aprocitentan doses that are much higher than the maximum recommended human dose, and no effects on fertility occurred (see section 5.3).

Decreased sperm count has been observed in patients taking other ERAs. It is not known if aprocitentan may adversely affect spermatogenesis in men.

In female rats, aprocitentan slightly increased pre-implantation loss (see section 5.3).

Aprocitentan has negligible influence on the ability to drive and use machines. However, adverse reactions (e.g., headache or hypotension) may occasionally occur that may influence the ability to drive and use machines.

Summary of safety profile

The most frequently reported adverse reactions with aprocitentan were oedema/fluid retention (9.1% [12.5 mg] and 18.4% [25 mg]) and haemoglobin decreased (3.7% [12.5 mg] and 1.2% [25 mg]) (see section 4.4).

Tabulated list of adverse reactions

The safety of aprocitentan was evaluated in one placebo-controlled Phase 3 clinical study (see section 5.1). In this study, 724 patients received aprocitentan, with 633 patients treated for at least 26 weeks, 192 patients for at least 47 weeks, and 99 patients for at least 48 weeks.

The frequency of adverse reactions is defined using the following convention: 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).

Table 1. Adverse reactions:

^a Upper respiratory tract infection includes pharyngitis, nasopharyngitis.
^b Haemoglobin decreased includes anaemia.
^c Hypersensitivity includes rash, erythema, allergic oedema, dermatitis allergic.
^d Dyspnoea includes dyspnoea exertional.
^e Oedema/fluid retention includes mainly oedema peripheral, fluid retention, face oedema.

Description of selected adverse reactions

Oedema/fluid retention

Oedema/fluid retention events appear to be dose-related (9.1% [12.5 mg] and 18.4% [25 mg] during the 4-week double-blind [DB] treatment.

Over the entire study, 0.8% of patients discontinued treatment of aprocitentan 25 mg due to oedema/fluid retention.

Actions to be taken if oedema/fluid retention occurs are described in section 4.4.

A mean increase in body weight of +0.4 kg and +0.6 kg was observed in patients on aprocitentan 12.5 and 25 mg, respectively, compared to –0.2 kg in patients on placebo during the 4-week DB treatment (part 1). This increase disappeared during the 32-week single-blind (SB) treatment (part 2).

Transaminases increased

Alanine/aspartate aminotransferase (ALT/AST) elevations >3 × ULN were reported in 0% and 0.4% of patients receiving JERAYGO 12.5 mg and 25 mg, respectively, compared to 0.9% in placebo patients during the initial 4-week DB treatment (part 1). 1.5% of patients reported these events during the 32-week SB treatment (part 2) when all subjects received 25 mg. 1.3% of patients reported these events during the 12-week double-blind withdrawal (DB-WD) treatment (part 3) on 25 mg, compared to 1.0% on placebo. There were no reports of patients with ALT and/or AST >3 × ULN and total bilirubin >2 × ULN in the study.

Hypersensitivity reactions

Cases of hypersensitivity reactions (i.e., rash, erythema, allergic oedema, dermatitis allergic) occurred within the first 2 weeks of treatment and were mild to moderate. There were 2 patients who discontinued treatment, 1 of whom was hospitalised.

Haemoglobin decreased

Mean haemoglobin at baseline was 13.9, 13.9, and 14.1 g/dL for aprocitentan 12.5 mg, 25 mg, and placebo, respectively. During the 4-week DB treatment (part 1), a mean decrease in haemoglobin of 0.80 and 0.85 g/dL was reported in patients receiving aprocitentan 12.5 and 25 mg, respectively, compared to a decrease of 0.4 g/dL in patients receiving placebo. At the end of the 32-week SB treatment (part 2), during which all patients received aprocitentan 25 mg, the mean decrease in haemoglobin remained unchanged at 0.87 g/dL compared to baseline. Reversibility of the effect was observed within 4 weeks after discontinuation.

A decrease from baseline in haemoglobin concentration to below 10 g/dL was reported in 6.4% of patients during the 48-week exposure to aprocitentan 25 mg. Of these patients, the range for haemoglobin at baseline was 10.3 to 15.4 g/dL.

Actions to be taken if haemoglobin decrease occurs are described in section 4.4.

Glomerular filtration rate decreased

Mean eGFR at baseline was 76.2, 76.7, and 76.2 mL/min/1.73 m² for aprocitentan 12.5 mg, 25 mg, and placebo, respectively. During the 4-week DB treatment (part 1), a mean decrease in eGFR of 1.2 and 2.4 mL/min/1.73 m² was reported in patients receiving aprocitentan 12.5 and 25 mg, respectively, compared to a decrease of 0.6 mL/min/1.73 m² in patients receiving placebo. At the end of the 32-week SB treatment (part 2), the mean decrease in eGFR was 2.3 mL/min/1.73 m²; it remained stable until the end of the study.

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 the national reporting system listed in Appendix V.

Not applicable.