Source: FDA, National Drug Code (US) Revision Year: 2024
Use of TRYVIO is contraindicated in pregnancy. To prevent pregnancy, patients who can become pregnant should use acceptable contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with TRYVIO [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
TRYVIO is contraindicated in patients who are hypersensitive to aprocitentan or any of its excipients [see Adverse Reactions (6.1)].
Based on data from animal reproduction studies with endothelin receptor antagonists (ERAs), TRYVIO can cause fetal harm when administered during pregnancy and is contraindicated for use in patients who are pregnant. Exclude pregnancy and ensure use of acceptable contraceptive methods prior to initiation of treatment with TRYVIO. Counsel patients who can become pregnant about the potential risk to a fetus. Patients should monitor for pregnancy monthly during treatment and one month after discontinuation of treatment and avoid pregnancy by using acceptable contraception methods prior to initiation of treatment with TRYVIO, during treatment, and for one month after the final dose of TRYVIO. If pregnancy is detected, discontinue TRYVIO [see Dosage and Administration (2.2), Contraindications (4.1), Warnings and Precautions (5.2,) Use in Specific Populations (8.1, 8.3)].
TRYVIO is available only through a restricted program under a REMS called the TRYVIO REMS because of the risk of embryo-fetal toxicity [see Contraindications (4.1), Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)].
Important requirements of the TRYVIO REMS include the following:
Elevations of aminotransferases and hepatotoxicity are known effects of ERAs, including TRYVIO. Elevations in alanine transaminase (ALT) or aspartate aminotransferase (AST) of greater than 5-fold upper limit of normal (ULN) were observed rarely in patients treated with aprocitentan in the clinical trial, including cases with positive rechallenge. There were no reports of patients with ALT and/or AST >3 × ULN and total bilirubin >2 × ULN or cases of liver failure observed in TRYVIO-treated patients in the clinical trials. To reduce the risk of potential serious hepatotoxicity, measure serum aminotransferase levels and total bilirubin prior to initiation of treatment and repeat during treatment periodically and as clinically indicated.
Do not initiate TRYVIO in patients with elevated aminotransferases (>3 × ULN) or moderate to severe hepatic impairment.
Advise patients with symptoms suggesting hepatotoxicity (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, scleral icterus, jaundice, dark urine, fever, or itching) to immediately stop treatment with TRYVIO and seek medical attention.
If sustained, unexplained, clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or if clinical symptoms of hepatotoxicity occur, discontinue TRYVIO.
Fluid retention and peripheral edema are known effects of ERAs, including TRYVIO [see Adverse Reactions (6.1)]. Edema/fluid retention was reported in 9% of TRYVIO-treated patients compared with 18% of patients receiving aprocitentan 25 mg (twice the recommended dose) and 2% on placebo in the clinical trial, requiring additional diuretic use in some patients. Older age and chronic kidney disease are risk factors for edema/fluid retention with TRYVIO. TRYVIO has not been studied in patients with heart failure New York Heart Association stage III–IV, unstable cardiac function, or with NTproBNP ≥500 pg/mL. TRYVIO is not recommended in these patients.
Monitor for signs and symptoms of fluid retention, weight gain, and worsening heart failure. If clinically significant fluid retention develops, treat appropriately, and consider discontinuation of TRYVIO.
Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in the clinical trial with TRYVIO. Hemoglobin decreases usually presented early, stabilized thereafter, and were reversible after discontinuation. A decrease in hemoglobin of >2 g/dL from baseline was observed in 7% of patients compared to 1% of placebo patients. A decrease to below 10.0 g/dL was observed in 3% of TRYVIO-treated patients compared to 0 patients taking placebo. Initiation of TRYVIO is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and periodically during treatment as clinically indicated [see Adverse Reactions (6.1)].
TRYVIO, like other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].
Clinically significant adverse reactions that appear in other sections of the labeling include:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of TRYVIO was evaluated in a placebo-controlled phase 3 clinical study (PRECISION, NCT03541174) in adults with uncontrolled BP (systolic blood pressure [SBP] ≥140 mmHg) despite the use of at least three antihypertensive medications.
In this study, 724 patients received any dose of 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 most frequently reported adverse reactions to TRYVIO during the 4-week doubleblind placebo-controlled treatment period (part 1) of the PRECISION study are presented in Table 1.
Table 1. Adverse reactions reported with a frequency of ≥2% in TRYVIO-treated patients and greater (≥1%) than in placebo-treated patients during the initial 4-week double-blind placebo-controlled treatment (part 1):
| Adverse Reaction | 12.5 mg N=243 % | Placebo N=242 % |
|---|---|---|
| Edema/fluid retention | 9.1 | 2.1 |
| Anemia | 3.7 | 0 |
During the initial 4-week double-blind placebo-controlled treatment period (part 1), 0.8% of patients experienced an adverse reaction of hypersensitivity (i.e., rash, erythema, allergic edema) on TRYVIO compared to no reports in patients treated with placebo. One patient experienced allergic dermatitis requiring hospitalization while receiving aprocitentan 25 mg.
Initiation of TRYVIO may cause an initial small decrease in estimated glomerular filtration rate (eGFR) that occurs within the first 6 weeks of starting therapy and then stabilizes.
In the initial 4-week double-blind treatment period, TRYVIO 12.5 mg caused a mean decrease of about 0.8 g/dL in hemoglobin compared to no change in the placebo patients.
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)]. 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.
There is a Pregnancy Safety Study that monitors pregnancy outcomes in women exposed to TRYVIO during pregnancy. Healthcare providers should report any prenatal exposure to TRYVIO by calling 1-866-429-8964.
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.
There are no data on the presence of aprocitentan in human milk, the effects on the breastfed infant, or the effect on milk production. In rats, aprocitentan was excreted into milk during lactation (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with TRYVIO.
A single 14C-radiolabeled macitentan dose of 3 mg/kg was given orally to lactating Wistar rats. Aprocitentan was consistently observed in milk samples across all collection times after oral administration.
Based on data from animal reproductive toxicity studies with other ERAs, TRYVIO can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4.1), Use in Specific Populations (8.1)].
Verify the pregnancy status of patients prior to initiating TRYVIO. Patients who can become pregnant should exclude pregnancy with a negative pregnancy test monthly during treatment, and one month after discontinuation of treatment with TRYVIO. The patient should contact their physician immediately if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to the patient, the pregnancy, and the fetus [see Warnings and Precautions (5.1), Dosage and Administration (2.2), Contraindications (4.1)].
Patients using TRYVIO who can become pregnant should use acceptable contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with TRYVIO [see Warnings and Precautions (5.1)].
Other ERAs have shown an adverse effect on spermatogenesis in humans and/or animals. TRYVIO, like other ERAs, may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see Warnings and Precautions (5.6), Nonclinical Toxicology (13.1)].
The safety and efficacy of TRYVIO in pediatric patients have not been established.
Of the total number of subjects in the PRECISION study of TRYVIO, 321 (44%) were 65 years and older, while 72 (10%) were 75 years and older. Edema/fluid retention was more common in these patients than younger patients [see Warnings and Precautions (5.4)].
No dose adjustment is required in patients over the age of 65 years [see Clinical Pharmacology (12.3)].
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 (12.3)]. Patients with renal impairment are at increased risk of edema/fluid retention [see Warnings and Precautions (5.4)].
No dose adjustment is required in patients with mild to severe renal impairment (eGFR ≥15 mL/min).
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 (12.3)].
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