Filspari (sparsentan)

If elevations in AST or ALT occur in patients receiving sparsentan, monitoring and treatment should be adjusted (see Table 1). Do not resume sparsentan therapy in patients who have experienced clinical symptoms of hepatotoxicity or in patients whose hepatic enzymes and bilirubin levels have not returned to baseline levels.

Table 1. Recommended Dosage Adjustment and Monitoring for Sparsentan in Patients with Transaminase Elevations

AST/ALT Levels Treatment and Monitoring Recommendations >3 times and <=8 times ULN Confirm AST/ALT elevations with repeat measurement. Once elevations are confirmed, temporarily interrupt treatment and monitor AST/ALT and bilirubin levels at least weekly, and international normalized ratio (INR) levels as needed, until levels return to baseline and the patient is asymptomatic. Do not resume sparsentan therapy if any of the following occurs without another identified cause: If re-initiating sparsentan, initiate at a dosage of 200 mg once daily, and reassess AST/ALT and bilirubin levels within 3 days. Monitor patients closely. The dosage may be increased to 400 mg once daily after 14 days, as tolerated. >8 times ULN Discontinue sparsentan therapy permanently if no other cause identified.

Sparsentan is administered orally. It is available as an oral tablet containing sparsentan 200 mg or 400 mg.

Administer sparsentan tablets whole with water once daily prior to the same meal (morning or evening) each day. If a dose of sparsentan is missed, skip the missed dose and take the next dose at the regularly scheduled time.

Store sparsentan at 20--25oC in the original container (excursions permitted between 15--30oC).

No dosing information is available for this tab.

In vitro, sparsentan both inhibits and induces cytochrome P-450 (CYP) 3A. Sparsentan is also an inducer of CYP2B6, 2C9, and 2C19.

Sparsentan is a substrate of CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) in vitro, but not a substrate of organic anion transporter polypeptide (OATP) 1B1 or 1B3.

At clinically relevant concentrations, sparsentan inhibits P-gp, BCRP, OATP1B3, and organic anion transporter (OAT) 3, but does not inhibit multidrug resistance-associated proteins (MRP), OATP1B1, sodium/taurocholate cotransporting polypeptide (NTCP), organic cation transporter (OCT) 2, OAT1, multidrug and toxin extrusion (MATE) 1, or MATE2K.

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

Sparsentan/Ace Inhibitors; Arbs; Eras; Aliskiren

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.

Sparsentan/Strong Cyp3a4 Inducers

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 metabolized by CYP3A4. Strong inducers of CYP3A4 may increase the metabolism of sparsentan.(1)

CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of sparsentan.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid concomitant use of sparsentan with strong CYP3A4 inducers.(1)

DISCUSSION: Coadministration of a single dose of sparsentan with rifampin (a strong CYP3A inducer) is predicted to decrease the concentration maximum (Cmax) and area-under-curve (AUC) of sparsentan by 23% and 47%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3)

Sparsentan/Strong Cyp3a4 Inhibitors

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: Strong inhibitors of CYP3A4 may inhibit the metabolism of sparsentan.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from sparsentan including hepatotoxicity, hypotension, hyperkalemia, and renal impairment.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with sparsentan should be avoided. If concurrent use cannot be avoided, interrupt therapy with sparsentan. When resuming sparsentan, consider dose titration.(1)

DISCUSSION: Co-administration of a single dose of sparsentan with itraconazole (a strong CYP3A4 inhibitor) increased concentration maximum (Cmax) and area-under-curve (AUC) of sparsentan by 25% and 174%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Strong & Moderate Cyp2c19 Inducers/Mavacamten

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: Strong and moderate inducers of CYP2C19 may increase the metabolism of mavacamten.(1-3)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP2C19 inducers with mavacamten may decrease the levels and effectiveness of mavacamten.(1-3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US and Canadian manufacturers of mavacamten state concomitant use of strong or moderate inducers of CYP2C19 is contraindicated.(1,2) The UK manufacturer of mavacamten states concomitant use with strong or moderate CYP2C19 inducers is dependent on CYP2C19 phenotype. Labeling recommends: -When initiating or increasing the dose of a strong inducer in patients who are CYP2C19 poor metabolizers, monitor patients closely and adjust mavacamten dose based on clinical response. The maximum recommended dose of mavacamten is 5 mg daily. -When initiating or increasing the dose a strong or moderate inducer in patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers, monitor patients closely and adjust mavacamten dose based on clinical response. -When discontinuing or decreasing the dose of a strong inducer in patients who are CYP2C19 poor metabolizers, decrease the dose of mavacamten from 5 mg to 2.5 mg, or pause therapy if dose is 2.5 mg. -When discontinuing or decreasing the dose of a strong or moderate inducer in patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers, decrease the dose of mavacamten by one dose level when on doses of 5 mg or higher. Maintain mavacamten dose when on 2.5 mg. -No dose adjustment is warranted with moderate inducers in patients who are CYP2C19 poor metabolizers.(3)

DISCUSSION: Concomitant use of mavacamten (a single 15 mg dose) with a strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted to decrease mavacamten area-under-curve (AUC) and maximum concentration (Cmax) by 87% and 22%, respectively, in CYP2C19 normal metabolizers, and by 69% and 4%, respectively, in CYP2C19 poor metabolizers. Moderate CYP2C19 inducers linked to this monograph include: dicloxacillin and sparsentan.(4,5)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Ace Inhibitors; Arbs/Lithium

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blocker (ARB)-induced sodium loss or volume depletion may result in decreased renal clearance of lithium.(1)

CLINICAL EFFECTS: Concurrent use of ACEI or ARBs may result in elevated lithium levels and lithium toxicity. Lithium has a narrow therapeutic range. Unintended increases in lithium concentrations may lead to lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, bradycardia, tinnitus, or nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.(1)

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: acute renal impairment, chronic renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ACEI, ARBs, NSAIDs, diuretics).(1) Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: If concurrent therapy cannot be avoided, monitor closely. Evaluate renal function and most recent lithium levels. If renal function is not stable, whenever possible delay initiation of concurrent therapy until renal function is stable. The onset of lithium toxicity due to concomitant therapy with an ACEI or ARB may be delayed for 3-5 weeks.(2) Patients receiving this combination should be observed for signs of lithium toxicity when the ACEI or ARB dose is increased or if additional risk factors for lithium toxicity emerge. If an ACEI or ARB is required in a patient stabilized on lithium therapy, check baseline lithium concentration, consider empirically lowering the lithium dose, then recheck lithium levels 5 to 7 days after ACEI or ARB initiation. Adjust lithium, ACEI or ARB dose as required and continue frequent (e.g. weekly) monitoring of lithium until levels have stabilized. If lithium is to be started in a patient stabilized on an ACEI or ARB, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged.(1) Monitor lithium concentrations frequently until stabilized on the combination. If an interacting drug is discontinued, the lithium level may fall. Monitor lithium concentration and adjust dose if needed.(1) Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: Elevated lithium levels and lithium toxicity have been reported during concomitant administration of lithium and an ACEI(3-17) or an ARB(18-20). Other factors, such as dehydration, acute or worsening of chronic renal impairment, or acute changes in sodium intake may increase the occurrence of a clinically important interaction.

Ace Inhibitors; Arbs/Sodium Phosphate Bowel Cleanser

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bowel cleansing with sodium phosphate causes dehydration, decreased intravascular volume and hyperphosphatemia, which increases phosphate levels in the renal tubules. Abnormally high levels of calcium and phosphate in the renal tubules may precipitate out, resulting in renal injury.(1)

CLINICAL EFFECTS: Use of sodium phosphate for bowel cleansing in patients maintained on angiotensin converting enzyme (ACE) inhibitors, angiotension receptor blockers (ARBs) may increase the risk of acute phosphate nephropathy, which is an acute kidney injury associated with deposits of calcium phosphate crystal in the renal tubules that may result in permanent renal function impairment. Acute phosphate nephropathy presents as acute kidney injury with minimal proteinuria and a bland urine sediment.(2) Use of sodium phosphate products at laxative doses has not been associated with acute kidney injury.(3)

PREDISPOSING FACTORS: Patients who may be at an increased risk of acute phosphate nephropathy include those who are over age 55; are hypovolemic or have decreased intravascular volume; have baseline kidney disease, bowel obstruction, or active colitis; and who are using medications that affect renal perfusion or function (such as diuretics, ACE inhibitors, ARBs, and possibly nonsteroidal anti-inflammatory drugs (NSAIDs).(2)

PATIENT MANAGEMENT: If possible, use an alternative agent for bowel cleansing.(1) Use sodium phosphate products with caution in patients taking medications that affect kidney function or perfusion, such as ACE inhibitors or ARBs. Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN, creatinine, and [in smaller, frail individuals] glomerular filtration rate). Instruct patients to drink sufficient quantities of clear fluids before, during, and after bowel cleansing and to avoid other laxatives that contain sodium phosphate. Consider hospitalization and intravenous hydration during bowel cleansing to support frail patients who may be unable to drink an appropriate volume of fluid or who may be without assistance at home.(2) Use of an electrolyte solution for rehydration may decrease the risk of acute phosphate nephropathy.(4,5)

DISCUSSION: Since May 2006, the FDA has received 20 reports of acute phosphate nephropathy associated with the use of Osmo Prep. Concomitant medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs (4).(2) In a retrospective review of colonoscopy patients, simultaneous use of ACE inhibitors or ARBs significantly increased the risk of acute kidney injury from oral sodium phosphate. Diuretic use was also a risk factor.(6) In a case series study of 21 cases of acute phosphate nephropathy in patients who had used oral sodium phosphate, 14 patients received an ACE inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7) Cases have also been reported with rectal products.(8)

Ace Inhibitors; Arbs/Trimethoprim

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), and trimethoprim have all been proven to increase serum potassium levels. The increase is achieved by reduction in potassium elimination by trimethoprim(1,2) and a decrease in angiotensin activity by ACE Inhibitors and ARBs. The use of these medications in combination can have an additive effect on serum potassium resulting in potentially dangerous levels.(1-5)

CLINICAL EFFECTS: Concurrent use of trimethoprim and ACE Inhibitors or Angiotensin Receptor Blockers may result in increased serum potassium levels,(1-5) which may be fatal.(2)

PREDISPOSING FACTORS: The interaction may be more significant in elderly patients and patients with renal insufficiency.(1)

PATIENT MANAGEMENT: Use trimethoprim with caution in patients maintained on ACE Inhibitors or ARBs. Patients using these medications concurrently should have their serum potassium monitored. In the elderly or renally impaired, alternative antibiotic therapy should be considered.

DISCUSSION: In a retrospective review of patients in Ontario maintained on an ACE inhibitor or ARB who were admitted to a hospital for hyperkalemia within 14 days of receiving a prescription for SMX-TMP, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantion, 371 patients were identified. More than half of the patients with hyperkalemia had received SMX-TMP. Patients receiving SMX-TMP had a 7-fold increased risk of hyperkalemia compared to patients receiving other antibiotics. No risk was found with the other antibiotics.(1) A retrospective review of patients in Ontario maintained on an ACE inhibitor or ARB examined those who died within 7 days of filling an outpatient prescription for amoxicillin, ciprofloxacin, norfloxacin, nitrofurantoin, or SMX-TMP. Patients receiving SMX-TMP had an increased risk of death (adjusted odds ratio 1.38) compared to amoxicillin. Risk was slightly higher at 14 days (adjusted odds ration 1.54). This corresponded to 3 sudden deaths within 14 days per 1000 SMX-TMP prescriptions.(2) A review of nine case reports of hyperkalemia with SMX-TMP found that 2 patients were receiving concurrent ACE inhibitors (enalapril and benazepril). One of these patients had severe hyperkalemia with a peak potassium level of 7.4 mEq/l.(3) Hyperkalemia has also been reported with concurrent SMX-TMP and enalapril(4) and with quinapril.(5)

Select Cyp2c19 Or Cyp3a4 Inducer/Esomeprazole; Omeprazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Proton pump inhibitors are primarily metabolized by CYP2C19, while CYP3A4 also plays a role in metabolism.(1,2) Enzalutamide, rifampin, and St. John's wort are moderate inducers of CYP2C19 and strong inducers of CYP3A4.(3,4) Apalutamide is a strong inducer of CYP2C19 and CYP3A4.(5) Efavirenz and pacritinib are moderate inducers of CYP2C19 and CYP3A4.(3,6) Sparsentan is a moderate inducer of CYP2C19.(8) Fexinidazole is a moderate inducer of CYP3A4.(3)

CLINICAL EFFECTS: Concurrent use of agents which induce both CYP2C19 and CYP3A4 decrease systemic exposure and may result in decreased effectiveness of proton pump inhibitors.(1-7)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid concurrent use of esomeprazole or omeprazole with CYP2C19 or CYP3A4 inducers.(1,2) Monitor patients receiving concurrent therapy for reduced proton pump inhibitor (PPI) effectiveness. Although specific dosing recommendations are not available, a higher dose of the proton pump inhibitor may be considered to maintain PPI efficacy.

DISCUSSION: In an interaction study, subjects with prostate cancer received omeprazole before and after enzalutamide 160 mg daily for at least 55 days. Enzalutamide decreased omeprazole area-under-curve (AUC) by 70.5%.(3,4) In an interaction study, rifampin 600 mg daily for 7 days decreased omeprazole AUC by 89.5%.(3,7) In an interaction study, pacritinib 200 mg twice daily at steady state decreased the Cmax and AUC of a single dose of omeprazole (20 mg) by 27% and 51%, respectively.(6) Concomitant use with sparsentan (moderate CYP2C19 inducer) decreased the exposure of omeprazole Cmax by 49% and AUC by 60%.(8) In an interaction study, St. John's wort decreased the maximum concentration (Cmax) and AUC of omeprazole by 37.5% and 49.6%, respectively. The Cmax and AUC of omeprazole sulfone (via CYP2C19) increased by 160.3% and 136.6%, respectively. The Cmax and AUC of 5-hydroxyomeprazole (via CYP3A4) increased by 38.1% and 37.2%, respectively.(9,10)

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

Ace Inhibitors; Arbs/Drospirenone

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

MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. ACE inhibitors and angiotensin II receptor antagonists may also increase potassium levels.(1)

CLINICAL EFFECTS: Concurrent use of drospirenone and ACE inhibitors or angiotensin II receptor antagonists may result in hyperkalemia.(1)

PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, potassium-sparing diuretics, heparin, and NSAIDs may increase potassium levels.(1)

PATIENT MANAGEMENT: Patients receiving drospirenone with either an ACE inhibitor or an angiotensin II receptor antagonist should have their serum potassium level checked during the first treatment cycle.(1)

DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of ACE inhibitors or angiotensin II receptor antagonists may also increase potassium levels.(1) In a study in 24 mildly hypertensive postmenopausal women who received concurrent drospirenone/estradiol (3 mg/1 mg) with enalapril (10 mg), mean serum potassium levels were 0.22 mEq/L higher than in the placebo group. On day 14 of concurrent therapy, the ratios for serum potassium maximum concentration (Cmax) and area-under-curve (AUC) were 0.955 and 1.010, respectively. No patient developed hyperkalemia.(1)

Ace Inhibitors; Arbs/Loop Diuretics

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

MECHANISM OF ACTION: The exact mechanism is unknown. The initial hypotensive effect of the ACE inhibitors is mainly the result of suppression of the renin-angiotensin-aldosterone system. The ACE inhibitors inhibit the formation of angiotensin II and angiotensin II receptor antagonists block the action of angiotensin II, thereby lowering aldosterone levels with subsequent sodium and water depletion. Agents such as the loop diuretics that cause sodium and water loss may exaggerate the hypotensive state.

CLINICAL EFFECTS: The addition of an ACE inhibitor to a patient receiving a loop diuretic may result in severe postural hypotension. This effect is transient and is not expected to occur during long-term dosing. Symptomatic hypotension may result in patients treated with loop diuretics who are started on an angiotensin II receptor antagonist. Concurrent use of a renin-angiotensin system (RAS) inhibitor with diuretics and NSAIDs may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Addition of an ACE inhibitor or an angiotensin II receptor antagonist to a patient already receiving a diuretic or who is sodium depleted. Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individual's susceptibility to AKI.

PATIENT MANAGEMENT: In patients without heart failure, it may be advisable to discontinue the diuretic, reduce the dose of the diuretic, or increase salt intake prior to the initiation of the ACE inhibitor. If hypotension occurs, place the patient in a supine position. Hypotension is most likely when the ACE inhibitor is initiated. However, if subsequent hypotension occurs, a dosage adjustment or discontinuation of one agent may be required. Intravascular volume depletion should be corrected in patients prior to the initiation of an angiotensin II receptor antagonist. Concurrent use of a RAS inhibitor with loop diuretics and NSAIDs should be used with caution and monitored closely for signs of AKI.

DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(4,5) In an observational study, current use of a triple therapy with a diuretic, RAS inhibitor, and NSAID, was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46). (6) Severe postural hypotension(1,2) and transient postural hypotension(3) has been reported in patients receiving concurrent captopril and furosemide. The effect is transient and may be more prevalent in patients who are sodium depleted.(8) Reversible renal failure(9) and decreased renal function(10) have been reported in patients receiving concurrent administration with enalapril and furosemide. In a study in which electrolytes were replaced with saline or Ringer's solution, no postural hypotension was noted; however, significant decreases in diastolic blood pressure occurred at three, four, and six hours after concurrent administration.(11)

Angiotensin Ii Receptor Blocker (Arb)/K+ Sparing Diuretics

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

MECHANISM OF ACTION: Angiotensin II receptor blockers (ARBs) may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium sparing diuretics with an ARB may result in hyperkalemia.

PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus.

PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with a potassium sparing diuretic and an ARB. In all patients taking eplerenone who start taking an an ARB, check serum potassium and creatinine levels after 3-7 days of concurrent therapy.

DISCUSSION: In a nested case-control study of heart failure patients receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of hyperkalemia was significantly associated with spironolactone use (odds ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20) In a systemic literature review and meta-analysis of 20 randomized controlled studies, it was found that treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L).(21) A retrospective cohort study in patients with hypertension, diabetes, and albuminuria between 2008 and 2018 examined the efficacy and safety of mineralocorticoid receptor antagonists eplerenone and spironolactone in combination with ACEI/ARB compared to ACEI/ARB alone. Hyperkalemia was more frequent in combination therapy patients (n=1,282) versus monotherapy (n=5,484) (22.3 vs 10.9 per 100 person-years for combination and monotherapy, respectively; HR = 1.78, 95% CI: 1.42, 2.24).(22) Several studies have indicated that serum potassium levels increase when ACE inhibitors and ARB therapy is initiated and decrease when the drug is lowered. There are case reports of hyperkalemia during concurrent therapy with ARBs and spironolactone and with aliskiren and spironolactone. Based on this data, serum potassium levels should be monitored in patients receiving concomitant ARBs with potassium sparing diuretics.

Angiotensin Ii Receptor Blocker (Arb)/Potassium Supplements

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

MECHANISM OF ACTION: Angiotensin II receptor blockers (ARBs) may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium supplements with ARBs may result in hyperkalemia.

PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus.

PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with potassium supplements and ARBs.

DISCUSSION: Several studies have indicated that serum potassium levels increase when ARB therapy is initiated and decrease when the drug is lowered. Based on this data, serum potassium levels should be monitored in patients receiving potassium supplements with ARBs.

Cyp2b6 And Selected Cyp3a4 Inducers/Levomethadone; Methadone

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

MECHANISM OF ACTION: CYP2B6 inducers, phenytoin, and St. John's wort may increase the metabolism of levomethadone and methadone.(1-7)

CLINICAL EFFECTS: Concurrent use of CYP2B6 inducers, phenytoin, or St. John's wort may result in decreased levels of levomethadone and methadone, which may result in decreased effectiveness and may precipitate withdrawal symptoms.(1-7)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Patients maintained on levomethadone or methadone may require dosage adjustments if a CYP2B6 inducer, phenytoin, or St. John's wort is initiated or discontinued. The effects of the interaction may last for several weeks after the discontinuation of the inducer.

DISCUSSION: In a study, efavirenz (600 mg daily) given for 3 weeks in patients on levomethadone led to a decrease in maximum concentration (Cmax) and area-under-curve (AUC) of levomethadone of 48 % and 57 %, respectively.(2) There are three case reports of patients in methadone maintenance programs who experienced withdrawal symptoms following the initiation of rifampin for tuberculosis therapy.(7,8) In one of these patients, the methadone clearance was measured at 8.97 ml/min/kg during concurrent administration of rifampin, compared with 2.11 ml/min/kg during methadone alone.(7) Other reports have documented that methadone-treated patients who received concurrent antituberculosis therapy which included rifampin experienced withdrawal symptoms while methadone-treated patients who received antituberculosis therapy which did not include rifampin did not.(9-12) Subsequently, it was determined that methadone plasma concentrations were decreased 33% to 68% in patients receiving concurrent rifampin compared with patients on non-rifampin regimens.(9,11-12) In a study in five patients maintained on methadone, the addition of phenytoin to their regimens resulted in moderately severe withdrawal symptoms and a decrease in the area-under-curve (AUC) for methadone. Methadone plasma concentrations returned to baseline levels two to three days after the discontinuation of phenytoin.(6) In a study in four patients in a methadone maintenance program, the addition of St. John's wort (900 mg daily) decreased methadone levels by 47% (range: 19%-60%). Two patients reported withdrawal symptoms.(7) CYP2B6 inducers linked to this monograph include: carbamazepine, dipyrone, isavuconazonium, ledipasvir/sofosbuvir, phenobarbital, primidone, rifampin, and sparsentan. Fosphenytoin, phenytoin and St. John's wort are also linked.

P-Glycoprotein (P-Gp) Inhibitors/Digoxin

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of digoxin at the levels of intestinal absorption, renal tubular secretion, and biliary-intestinal secretion.(1)

CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels and toxicities of digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin concentrations before initiating concomitant use with P-gp inhibitors and continue monitoring serum digoxin concentrations as recommended in the prescribing information for digoxin.(1) When digoxin levels are expected to be increased by over 50%, the manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 30-50% or by modifying the dosing frequency to reduce digoxin concentrations.(1) When digoxin levels are expected to be increased by less than 50%, the manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 15-30% or by modifying the dosing frequency to reduce digoxin concentrations.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: Digoxin is a known substrate of P-gp. Inhibitors of P-gp may increase toxicity of digoxin.(1) In a clinical study, elacestrant increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by 1.1-fold and 1.3-fold, respectively.(3,4) In another clinical study, imlunestrant increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by 1.4-fold and 1.6-fold, respectively.(5) In another clinical study, maribavir increased the AUC and Cmax of digoxin by 1.2-fold and 1.25-fold, respectively.(6) Inhibitors of P-gp linked to this monograph include: abrocitinib, aumolertinib, capmatinib, daraxonrasib, elacestrant, enzalutamide, imlunestrant, maribavir, selpercatinib, sparsentan, sotorasib, vepdegestrant, and vibegron.(2-8)

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)

Sparsentan/Nsaids; Salicylates

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

MECHANISM OF ACTION: Sparsentan is an endothelin and angiotensin II receptor antagonist.(1) Angiotensin II receptor blockers can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate. NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction.

CLINICAL EFFECTS: Concurrent use of sparsentan with NSAIDs (including selective COX-2 inhibitors) may result in renal hypoperfusion and deterioration of renal clearance, including possible acute kidney injury (AKI). These effects are usually reversible.(1)

PREDISPOSING FACTORS: Patients older than 75 years old, with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion (including from diuretic use and dehydration) may be at greater risk for AKI.(1-3)

PATIENT MANAGEMENT: Monitor for signs of worsening renal function if an NSAID (including selective COX-2 inhibitors) is used concurrently with sparsentan. If renal function deteriorates, the NSAID may need to be discontinued.(1)

DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(2,3) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(4)

*Pregnancy.

*Concomitant use with angiotensin receptor blockers (ARBs), endothelin receptor antagonists (ERAs), or aliskiren.

• Pregnancy

• Disease of liver

• Chronic heart failure
• Hyperkalemia
• Hypotension
• Hypovolemia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Renal artery stenosis

The most common adverse effects (occurring in >=5% of patients) are peripheral edema, hypotension (including orthostatic hypotension), dizziness, hyperkalemia, anemia, and acute kidney injury.

More Frequent

• Anemia
• Hyperkalemia
• Hypotension
• Orthostatic hypotension

Less Frequent

• Abnormal hepatic function tests
• Increased alanine transaminase
• Increased aspartate transaminase

Rare or Very Rare

• Drug-induced hepatitis

More Frequent

• Dizziness
• Peripheral edema

Less Frequent

• Kidney disease with reduction in glomerular filtration rate (GFr)

No enhanced messaging available.

Safety and efficacy of sparsentan have not been established in pediatric patients.

Available data from reports of pregnancy in clinical trials with sparsentan are not sufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Clinical data from postmarketing reports and published literature with endothelin receptor antagonists in the same class as sparsentan have not identified an increased risk of fetal harm; however, these data are limited. Animal reproductive data indicate that sparsentan may cause fetal harm, including birth defects and fetal death, when administered during pregnancy. Sparsentan is therefore contraindicated for use in pregnant individuals.

Following oral administration of sparsentan to pregnant rats during organogenesis at 10 times the MRHD in mg/day, teratogenic effects (e.g., craniofacial malformations, skeletal abnormalities, embryo-fetal lethality, decreased fetal weights) were observed in offspring. In pregnant rats and rabbits, teratogenicity and/or developmental toxicities associated with sparsentan were attributed to the antagonistic effects on endothelin type A and angiotensin II type 1 receptors.

Perform pregnancy testing prior to initiation of sparsentan treatment. Apprise patients of the potential hazard to the fetus if sparsentan is used during pregnancy.

It is not known if sparsentan is present in human milk. The effects on the breast-fed infant and on milk production are also unknown.

Advise patients to avoid breast-feeding while receiving sparsentan due to the potential for adverse reactions (e.g., hypotension) in the breast-fed infant.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In the PROTECT study, 7.4% of patients receiving sparsentan were >=65 years of age. No overall differences in safety or effectiveness were observed between geriatric patients and younger adults.