Version November 2024
Aprocitentan can cause major birth defects if used by pregnant patients. In patients who can become pregnant, obtain a negative pregnancy test prior to initiation of aprocitentan and counsel patients to take monthly pregnancy tests during treatment and one month after discontinuation of aprocitentan. To prevent pregnancy, patients who can become pregnant should use acceptable methods of contraception before the start of, during, and for one month after stopping treatment.
Because of the risk of birth defects, aprocitentan is only available through a restricted program called the TRYVIO Risk Evaluation and Mitigation Strategy (REMS).
Dosage guidance:
Safety: In patients of reproductive potential, confirm negative pregnancy test prior to initiation, monthly throughout treatment, and 1 month after discontinuation of therapy.
Hypertension: Oral: 12.5 mg once daily.
Missed doses: If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take 2 doses on the same day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function: Oral:
eGFR ≥15 mL/minute: No dosage adjustment necessary.
eGFR <15 mL/minute: Use not recommended.
Dialysis: Use not recommended.
Hepatic impairment prior to treatment initiation:
Baseline ALT or AST >3 × ULN: Initiation of therapy is not recommended.
Child-Turcotte-Pugh class A: Oral:No dosage adjustment necessary.
Child-Turcotte-Pugh class B and C: Oral: Use not recommended.
Hepatotoxicity during treatment: Discontinue treatment in patients who develop symptoms of hepatic injury (eg, anorexia, dark urine, fatigue, fever, itching, jaundice, nausea, right upper quadrant pain, vomiting) or who experience sustained, clinically relevant aminotransferase elevations, or if aminotransferase elevations are accompanied by elevated bilirubin (>2 × ULN).
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
1% to 10%:
Cardiovascular: Edema (≤9%; including peripheral edema)
Endocrine & metabolic: Fluid retention (≤9%)
Hematologic & oncologic: Anemia (4%)
<1%: Hypersensitivity: Hypersensitivity reaction (including allergic angioedema)
Frequency not defined: Hepatic: Hepatotoxicity, increased serum transaminases (including increased serum alanine aminotransferase, increased serum aspartate aminotransferase)
Hypersensitivity to aprocitentan or any component of the formulation; pregnancy.
Concerns related to adverse effects:
• Fluid retention/peripheral edema: Development of fluid retention and peripheral edema may occur. Risk factors include older age and chronic kidney disease. Use is not recommended in patients with heart failure New York Heart Association class III to IV, unstable cardiac function, or N-terminal prohormone brain natriuretic peptide ≥500 pg/mL.
• Hematologic effects: A reduction in hematocrit/Hb may occur early in therapy with subsequent stabilization. Use is not recommended in patients with severe anemia.
• Hepatic effects: Increases in serum liver aminotransferases and hepatotoxicity have been reported.
• Spermatogenesis: May be reduced.
Special populations:
• Pregnancy: Due to the risk of embryo-fetal toxicity, patients should avoid pregnancy during use by using acceptable contraception methods; discontinue therapy if pregnancy is detected.
• REMS program: Only available through restricted Tryvio (REMS) Program because of embryo-fetal toxicity risks. Prescribers and pharmacies must also be enrolled in the program. Patients of reproductive potential must be able to comply with pregnancy testing requirements of the program. Call 1-866-429-8964 or visit https://www.tryviorems.com for more information.
Tryvio: FDA approved March 2024; availability anticipated in 2nd half of 2024.
Oral: Swallow tablet whole. May be administered with or without food.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Tryvio: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217686s000lbl.pdf#page=18
Hypertension: May be used in patients whose BP is not adequately controlled on other antihypertensive medications.
Apresoline, aprepitant.
Substrate of UGT1A1, UGT2B7
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Belumosudil: May increase the serum concentration of UGT1A1 Substrates. Management: Avoid coadministration of belumosudil with substrates of UGT1A1 for which minimal concentration increases can cause serious adverse effects. If coadministration is required, dose reductions of the UGT1A1 substrate may be required. Risk D: Consider therapy modification
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Flunarizine: May enhance the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Iloperidone: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Indoramin: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Isocarboxazid: May enhance the antihypertensive effect of Antihypertensive Agents. Risk X: Avoid combination
Levodopa-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. Risk C: Monitor therapy
Loop Diuretics: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Mitapivat: May decrease the serum concentration of UGT1A1 Substrates. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Prazosin: Antihypertensive Agents may enhance the hypotensive effect of Prazosin. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Sparsentan: May enhance the adverse/toxic effect of Endothelin Receptor Antagonists. Risk X: Avoid combination
Terazosin: Antihypertensive Agents may enhance the hypotensive effect of Terazosin. Risk C: Monitor therapy
Urapidil: Antihypertensive Agents may enhance the hypotensive effect of Urapidil. Risk C: Monitor therapy
Evaluate pregnancy status prior to use. Patients who could become pregnant must have a negative pregnancy test prior to initiating treatment with aprocitentan, monthly during treatment, and 1 month after aprocitentan is discontinued.
Patients who could become pregnant should use acceptable contraception prior to starting aprocitentan, during aprocitentan treatment, and for 1 month after discontinuing aprocitentan. Acceptable forms of contraception include an IUD, contraceptive implant, tubal sterilization, or a combination of a hormone method plus a barrier method, or 2 barrier methods. When a hormone method is chosen, a barrier method must also be used. If the patient's partner has had a vasectomy, a hormone or barrier method must also be used. Patients should notify prescriber of changes in reproductive status. Health care providers should counsel patients on use of emergency contraception.
Aprocitentan may decrease spermatogenesis; it is not known if this is reversible once aprocitentan is discontinued.
Based on data from animal reproduction studies, in utero exposure to may cause fetal harm including embryo-fetal toxicity, birth defects, and fetal death.
Aprocitentan is contraindicated in patients who are pregnant; discontinue if pregnancy occurs during treatment.
Data collection to monitor outcomes from perinatal exposure to aprocitentan is ongoing. Health care providers should enroll patients exposed to aprocitentan during pregnancy in the pregnancy safety study (1-866-429-8964).
It is not known if aprocitentan is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.
Pregnancy test in patients of childbearing potential (prior to initiation, monthly, and 1 month after discontinuation); signs and symptoms of liver injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, scleral icterus, jaundice, dark urine, fever, or itching); ALT/AST (baseline, repeat as clinically indicated); total bilirubin (baseline; repeat as clinically indicated); Hb (baseline, as clinically indicated); fluid retention, weight gain, worsening heart failure).
Blocks endothelin (ET)-1 from binding to endothelin receptor subtypes ETA and ETB. Stimulation of these receptors is associated with vasoconstriction, fibrosis, cell proliferation, hypertrophy, and inflammation.
Distribution: Vd: ~20 L.
Protein binding: >99%, primarily to albumin.
Metabolism: Hepatic by UGT1A1- and UGT2B7-mediated N-glucosidation and non-enzymatic hydrolysis.
Half-life elimination: ~41 hours.
Time to peak: 4 to 5 hours.
Excretion: Urine: ~52% (0.2% as unchanged drug); feces: 25% (6.8% as unchanged drug).
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