Tryvio (aprocitentan)

No dosing information is available for this tab.

Aprocitentan is available as tablets containing 12.5 mg of the drug.

Administer aprocitentan with or without food. Swallow tablets whole.

If a dose of aprocitentan is missed, skip the missed dose and take the next dose at the regularly scheduled time; do not double doses to make up for a missed dose.

Store aprocitentan tablets at 20-25degreesC (excursions permitted between 15-30degreesC). Store in the original package. Dispense to patient in the original container only. Replace cap securely each time after opening; do not discard dessicant. Protect from light and moisture.

No dosing information is available for this tab.

In vitro, aprocitentan inhibits cytochrome P-450 (CYP) isoenzyme 3A4 and all members of the CYP2C family, but does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1. Aprocitentan induces CYP3A4, but does not induce CYP1A2 or CYP2C9. Aprocitentan is both a substrate for and an inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and UGT2B7.

In vitro, aprocitentan is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). However, inhibitors of P-gp and BCRP are not expected to impact aprocitentan pharmacokinetics.

In vitro, aprocitentan inhibits BCRP, bile salt export pump (BSEP), and sodium taurocholate co-transporting polypeptide (NTCP), but does not inhibit P-gp, organic cation transporter (OCT) 1, OCT2, human multidrug and toxin extrusion (MATE) 1, or MATE2K. At therapeutic concentrations, aprocitentan does not inhibit organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, or OATP1B3.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Ace Inhibitors; Arbs; Eras; Aliskiren/Sparsentan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sparsentan is an antagonist of the endothelin type A receptor and the angiotensin II type 1 receptor which are thought to contribute to the pathogenesis of IgA nephropathy.(1) Coadministration with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) may result in additive inhibition of angiotensin. RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

CLINICAL EFFECTS: Concurrent use of sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) may result in hypotension, syncope, hyperkalemia, and changes in renal function (including renal failure).(1)

PREDISPOSING FACTORS: Patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion may be at risk of developing acute kidney injury on sparsentan.(1) Patients with advanced kidney disease or taking concomitant potassium-increasing drugs (e.g., potassium supplements, potassium-sparing diuretics), or using potassium-containing salt substitutes are at increased risk for developing hyperkalemia.(1)

PATIENT MANAGEMENT: Do not coadminister sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs). Prior to initiating treatment with sparsentan, discontinue use of renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs).(1) RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

DISCUSSION: The US manufacturer of sparsentan states that concomitant use of sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) is contraindicated.(1) RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Selected Antihypertensive Agents/Selected Maois

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both MAOIs and antihypertensive agents may increase the risk of postural hypotension.(1,2)

CLINICAL EFFECTS: Postural hypotension may occur with concurrent therapy of MAOIs and antihypertensive agents.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of phenelzine states all patients should be followed closely for symptoms of postural hypotension. Hypotensive side effects have occurred in patients who have been hypertensive and normotensive, as well as hypotensive at initiation of phenelzine.(1) The manufacturer of tranylcypromine states hypotension has been observed most commonly but not exclusively in patients with pre-existing hypertension. Tranylcypromine doses greater than 30 mg daily have a major side effect of postural hypotension and can lead to syncope. Gradual dose titration is recommended to decrease risk of postural hypotension. Combined use with other agents known to cause hypotension have shown to have additive side effects and should be monitored closely.(2) Monitor the patient for signs and symptoms of postural hypotension including dizziness, lightheadedness, or weakness, especially upon standing. Monitor blood pressure as well as orthostatic vitals and adjust antihypertensive therapy, including decreasing the dose, dividing doses, or scheduling doses at bedtime, as needed to maintain goal blood pressure. If blood pressure remains hypotensive, consider decreasing the dose of phenelzine or tranylcypromine. In some cases, discontinuation of one or both agents may be necessary.(3) Normotensive patients on stable antihypertensive therapy who are started on either phenelzine or tranylcypromine may be at increased risk for hypotension. Hypertensive patients on stable phenelzine or tranylcypromine who require antihypertensive therapy would be at decreased risk for hypotension.

DISCUSSION: A review article describes the pharmacology of phenelzine and tranylcypromine as non-selective MAOIs which inhibit both type A and type B substrates. Orthostatic hypotension is described as the most common MAOI side effect and usually occurs between initiation and the first 3-4 weeks of therapy.(3) In a double-blind study, 71 patients were randomized to receive a 4-week trial of either tranylcypromine, amitriptyline, or the combination. The number of patients reporting dizziness at 4 weeks was not different between the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%; combination 66.7%). Blood pressure (BP) assessment noted a significant drop in standing BP in the tranylcypromine group compared to baseline (systolic BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02). Combination therapy also had a significant drop in standing BP compared to baseline (systolic BP change = -9 mmHg; p<0.02). Patients receiving amitriptyline had no significant change in BP from baseline at 4 weeks. All three groups had a trend toward increasing orthostatic hypotension in BP changes from lying to standing. The change in orthostatic hypotension was significant in the amitriptyline group with an average systolic BP orthostatic drop of -9 mmHg (p<0.05).(4) A randomized, double-blind study of 16 inpatients with major depressive disorder were treated with either phenelzine or tranylcypromine. Cardiovascular assessments were completed at baseline and after 6 weeks of treatment. After 6 weeks, 5/7 patients (71%) who received phenelzine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change p=0.02 and diastolic change p=0.02). After 6 weeks, 6/9 patients (67%) who received tranylcypromine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg, respectively; systolic change p=0.09 and diastolic change p=0.07).(5) Selected MAOIs linked to this monograph include: phenelzine and tranylcypromine. Selected antihypertensive agents include: ACE inhibitors, alpha blockers, ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine, hydralazine, moxonidine, and sparsentan.

Selected Antihypertensives And Vasodilators/Apomorphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

Selected Antihypertensives/Tizanidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4)

*Pregnancy.

*Hypersensitivity to aprocitentan or any of its excipients.

• Pregnancy

• Anemia
• Chronic heart failure
• Hyperbilirubinemia

• Disease of liver

Adverse effects reported in >=2% of patients receiving aprocitentan include edema/fluid retention and anemia.

There are no severe adverse reactions for this drug.

More Frequent

• Anemia
• Edema

Rare or Very Rare

• Allergic dermatitis
• Erythema
• Skin rash

No enhanced messaging available.

Safety and effectiveness of aprocitentan in pediatric patients have not been established.

Based on animal reproductive data, aprocitentan can cause embryo-fetal toxicity (including birth defects and fetal mortality) when administered during pregnancy. Aprocitentan is contraindicated during pregnancy.

Available data from postmarketing reports and published literature over decades of use with ERAs in the same class as aprocitentan have not identified an increased risk of major birth defects; however, these data are limited.

Counsel patients who can become pregnant that acceptable methods of contraception must be used before treatment with aprocitentan, during treatment, and for 1 month after treatment discontinuation.

Advise pregnant patients of the potential fetal risk with aprocitentan.

No data are available on the presence of aprocitentan in human milk, the effects of the drug on the breast-fed infant, or the effect on milk production. Aprocitentan is excreted into the milk of lactating rats; therefore, it is likely that the drug will be present in human milk.

Because of the potential for serious adverse reactions in breast-fed infants, advise women not to breast-feed during treatment with aprocitentan.

No dosage adjustment of aprocitentan is necessary in geriatric patients >65 years of age. In clinical trials, edema/fluid retention occurred more frequently in geriatric patients compared to younger adults.

In the PRECISION trial, 44% of patients were >=65 years of age, while 10% were >=75 years of age. Edema/fluid retention occurred more frequently in geriatric patients compared to younger adults.