Aprocitentan

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.

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).

Patients with underlying renal impairment (eGFR <60 mL/min/1.73 m²) or pre-existing heart failure taking aprocitentan 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.

Aprocitentan has not been studied in patients with eGFR <15 mL/min or in patients undergoing dialysis. Aprocitentan is not recommended in these patients.

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

Initiation of aprocitentan 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 aprocitentan.

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. Aprocitentan 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 aprocitentan if patients experience CV events while on treatment should be assessed on an individual basis.

Aprocitentan is not recommended in patients with elevated aminotransferases (>3 × upper limit of normal [ULN]). Liver enzyme tests should be obtained prior to initiation of aprocitentan.

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, aprocitentan is contraindicated during pregnancy.

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. Aprocitentan is contraindicated during breast-feeding.

Use in women of childbearing potential/Contraception in females

Aprocitentan 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, aprocitentan must be discontinued.

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.

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.

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.

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]).

Tabulated list of adverse reactions

The safety of aprocitentan was evaluated in one placebo-controlled Phase 3 clinical study. 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).

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.

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 aprocitentan 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.

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.