Aprocitentan
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From MedlinePlus, U.S. National Library of Medicine
Boxed warning
WARNING: EMBRYO-FETAL TOXICITY TRYVIO is contraindicated for use during pregnancy because it may cause fetal harm if used by pregnant patients. Therefore in patients who can become pregnant, exclude pregnancy prior to initiation of TRYVIO. Advise use of effective contraception before the start of TRYVIO, during treatment and for one month after stopping treatment. When pregnancy is detected, discontinue TRYVIO as soon as possible [see Dosage and Administration (2.2) , Contraindications (4.1) , Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ] . WARNING: EMBRYO–FETAL TOXICITY See full prescribing information for complete boxed warning.
Based on animal data TRYVIO may cause fetal harm if used by pregnant patients and is contraindicated in pregnancy. ( 4.1 , 5.1 , 8.1 ) For patients who can become pregnant, exclude pregnancy prior to initiation of treatment with TRYVIO. ( 2.2 , 5.1 , 8.3 ) Use effective contraception prior to initiation of treatment, during treatment, and for one month after stopping TRYVIO. ( 2.2 , 4.1 , 5.1 , 8.3 ) When pregnancy is detected, discontinue TRYVIO as soon as possible ( 5.1 )
Endothelin Receptor Antagonist
Dosing in kidney impairment
Renal Impairment TRYVIO is not recommended in patients with kidney failure (eGFR <15 mL/min) or on dialysis. The effect of kidney failure (eGFR <15 mL/min) or dialysis on aprocitentan pharmacokinetics is unknown [see Clinical Pharmacology ] . Patients with renal impairment are at increased risk of edema/fluid retention [see Warnings and Precautions ] .
No dose adjustment is required in patients with mild to severe renal impairment (eGFR ≥15 mL/min).
Dosing in liver impairment
Hepatic Impairment TRYVIO is not recommended in patients with moderate and severe hepatic impairment (Child-Pugh class B and C) because these patients may be at increased risk for poor outcomes from hepatotoxicity. No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A) [see Clinical Pharmacology ] .
Contraindications
Pregnancy ( 4.1 ) Hypersensitivity ( 4.2 )
4.1 Pregnancy Use of TRYVIO is contraindicated in patients who are pregnant [see Dosage and Administration (2.2) , Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] .
4.2 Hypersensitivity TRYVIO is contraindicated in patients who are hypersensitive to aprocitentan or any of its excipients [see Adverse Reactions (6.1) ] .
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on animal reproduction studies with other ERAs, TRYVIO can cause embryo-fetal toxicity, including birth defects and fetal death when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4.1) ] . Available data from post-marketing reports and published literature over decades of use with endothelin receptor antagonists in the same class as TRYVIO have not identified an increased risk of fetal harm; however, these data are limited.
Methodological limitations of these post-marketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal endothelin receptor antagonist use. Administration of macitentan, where approximately ≥50% of total exposure was to aprocitentan, was teratogenic in rats and rabbits at all doses tested (see Data ).
Available data from reports of pregnancy in clinical trials with TRYVIO are insufficient to rule out a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Advise pregnant patients of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data Animal Data In embryo-fetal development toxicity studies in pregnant rats and rabbits given macitentan (for which aprocitentan is a major metabolite) during the period of major organogenesis, cardiovascular and mandibular arch fusion malformations were observed at all doses studied. The lowest doses in rats and rabbits produced aprocitentan exposures that were equivalent to and 15-fold, respectively, the clinical exposures at the maximum recommended human dose (MRHD) based on area under the curve (AUC).
In pre- and post-natal development studies, female rats given macitentan (for which aprocitentan is a major metabolite) from late pregnancy through lactation showed reduced pup survival and impairment of the male fertility of the offspring at all doses. The lowest dose produced aprocitentan exposures approximately 2-fold the clinical exposures at the MRHD based on AUC.
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
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