Prestalia (perindopril arginine/amlodipine besylate)

Dosage of amlodipine besylate and amlodipine benzoate is expressed in terms of amlodipine.

Amlodipine is administered orally (as tablets, solution, or suspension) without regard to meals, preferably at the same time each day. Amlodipine is also commercially available in fixed combination with benazepril (e.g., Lotrel(R)), olmesartan medoxomil (e.g., Azor(R)), olmesartan medoxomil and hydrochlorothiazide (e.g., Tribenzor(R)), telmisartan, valsartan (e.g., Exforge(R)), valsartan and hydrochlorothiazide (e.g., Exforge(R) HCT), and atorvastatin (e.g., Caduet(R)). See the full prescribing information for additional administration instructions for each specific combination product.

If a dose of amlodipine is missed, the missed dose may be administered as soon as possible. If the dose is missed for more than 12 hours, do not take the dose and resume treatment with the next scheduled dose.

Amlodipine besylate tablets: Store the tablets at 15-30degreesC; dispense in a tight, light-resistant container.

Amlodipine besylate oral solution (Norliqva(R)): Store the oral solution at 20-25degreesC (excursions permitted to 15-30degreesC). Store and dispense in the original packaging (amber glass bottle).

Amlodipine benzoate oral suspension (Katerzia(R)): Shake the suspension well and measure each dose with a calibrated measuring device; do not use a household teaspoon or tablespoon. Store the oral suspension at 2-8degreesC and protect from light. Avoid freezing and excessive heat.

Perindopril erbumine is commercially available as 2 mg, 4 mg, and 8 mg tablets. Perindopril is administered orally once or twice daily. In clinical studies, administration of the drug in 2 divided doses generally was only slightly more effective than once-daily dosing.

Store perindopril tablets at 20-25degreesC (excursions permitted to 15-30degreesC). Protect from moisture.

No dosing information is available for this tab.

Amlodipine is a weak inhibitor of cytochrome P-450 (CYP) 3A isoenzymes.

When amlodipine is used in fixed combination with other drugs, interactions associated with the concomitant agent(s) must be considered in addition to those associated with amlodipine.

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

Ace Inhibitors/Sacubitril

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: Sacubitril is a neprilysin inhibitor. Overlapping inhibition of Angiotensin Converting Enzyme (ACE) and neprilysin may increase the risk of angioedema.(1,2)

CLINICAL EFFECTS: Concurrent use may result in angioedema.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of sacubitril and an ACE inhibitor is contraindicated. Allow a 36 hour washout period when switching between an ACE inhibitor and sacubitril.(1-3) Monitor patients for signs of angioedema (swelling of the face, lips, tongue, and/or throat).(2)

DISCUSSION: Higher incidence of angioedema was seen in clinical trials with omapatrilat, a combined ACE and neprilysin inhibitor. In the OCTAVE trial, the incidence and severity of angioedema was worse with omapatrilat (2.2%) than with enalapril (0.7%).(2) For this reason, overlap of sacubitril, a neprilysin inhibitor, with an ACE inhibitor is contraindicated and a 36 hour washout period is recommended when switching agents. The 36 hour window is designed to cover at least three half-lives of all ACE inhibitors.(1)

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.

Amlodipine/Simvastatin (>20 Mg)

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: Amlodipine may inhibit the metabolism of simvastatin by CYP3A4.(1-7) Levamlodipine is the active isomer of amlodipine.(8)

CLINICAL EFFECTS: Concurrent amlodipine may result in elevated levels of simvastatin,(1-7) which may result in myopathy and rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with amlodipine.(1-4) Consider separating the administration times of amlodipine and simvastatin in patients receiving concurrent therapy with amlodipine and simvastatin doses of 20 mg or less.(5) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: In a study in 8 patients with hypercholesterolemia and hypertension, 4 weeks of concurrent administration of amlodipine (5 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of simvastatin (5 mg daily) by 43% and 28%, respectively. There were no changes in the lipid-lowering affects of simvastatin.(6) In a study in 17 subjects, administration of amlodipine (5 mg daily) 4 hours after simvastatin (5 mg daily) resulted in Cmax and AUC values of simvastatin that were 63.2% and 66.0%, respectively, of values obtained with simultaneous dosing.(5) Acute renal failure and rhabdomyolysis was reported in patient maintained on amlodipine and alprazolam two days after beginning the maximal dose of simvastatin.(7)

Amlodipine; Levamlodipine/Conivaptan

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: Conivaptan may inhibit the metabolism of amlodipine via CYP3A4.(1) Levamlodipine is the active isomer of amlodipine.(2)

CLINICAL EFFECTS: Concurrent use of amlodipine or levamlodipine and conivaptan may result in increased levels of amlodipine or levamlodipine, which may lead to increased clinical effects and toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of conivaptan states that concurrent use of agents primarily metabolized by CYP3A4, such as amlodipine or levamlodipine, should be avoided. Amlodipine or levamlodipine may be initiated no sooner than 1 week after the infusion of conivaptan is completed.(1)

DISCUSSION: Conivaptan is a potent inhibitor of CYP3A4. In an evaluation of the combination of oral conivaptan (80 mg/day) and amlodipine, the area-under-curve (AUC) and half life of amlodipine were both increased 2-fold.(1)

Selected Nephrotoxic Agents/Bacitracin

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: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3)

CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3)

PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1)

PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3)

DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3)

Weak Cyp3a4 Inhibitors/Lemborexant (> 5 Mg)

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: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(1,3)

Weak Cyp3a4 Inhibitors/Ubrogepant (> 50 Mg)

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: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib. (3,4)

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

Ace Inhibitors/Mtor Inhibitors

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

MECHANISM OF ACTION: ACE inhibitors cause reduced bradykinin metabolism, leading to an increase in bradykinin which can cause vasodilation. mTOR inhibitors may also cause a reduction in bradykinin metabolism.

CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk.

PREDISPOSING FACTORS: History of previous angioedema.

PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and mTOR inhibitor. Consider switching the patient to an angiotensin receptor blocker. Monitor patients receiving concurrent therapy with ACE inhibitors and mTOR inhibitors closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately.

DISCUSSION: A retrospective, single center analysis looked at renal allograft recipients treated with mTOR inhibitors and ACE inhibitors over an 8 year-period. Out of 137 patients on concomitant ACE inhibitor and mTOR inhibitor therapy, 9 patients (6.6%) developed angioedema. Concomitant ACE inhibitor and mTOR inhibitor therapy increased the risk of developing angioedema 3.7-fold. Eight of these patients tolerated therapy with an angiotensin receptor blocker (ARB). 2 patients (1.2%) on concomitant mTOR inhibitor and ARB therapy developed angioedema. Treatment with an ACE inhibitor or mTOR inhibitor alone resulted in a significantly lower incidence of angioedema.(1) In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor.(2) There are case reports of patients on concomitant ACE inhibitor and sirolimus/everolimus that developed angioedema. In the majority of cases, patients had tolerated chronic therapy with an ACE inhibitor before the addition of sirolimus/everolimus.(3-7) The interaction may be dose-dependent.(7)

Ace Inhibitors; Arbs/Aliskiren

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

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: In the ALTITUDE study, concurrent use of aliskiren for 18-24 months in patients maintained on either an ACE inhibitor or an ARB resulted in an increase in non-fatal stroke, renal complications, hyperkalemia, and hypotension.(1,2)

PREDISPOSING FACTORS: Patients with Type II diabetes and/or renal impairment may be at a higher risk from this combination.(1)

PATIENT MANAGEMENT: Novartis no longer recommends the concurrent use of aliskiren with either an ACE inhibitor or an ARB.(1,3) Hypertension regimens of patients receiving concurrent therapy should be re-evaluated.(1) Concurrent use of aliskiren in diabetic patients receiving either an ACE inhibitor or an ARB is contraindicated.(2,4) Avoid the combination in patients with CrCl less than 60 ml/min.(5)

DISCUSSION: ALTITUDE was a multinational study designed to evaluate the use of aliskiren for more than 1 year in patients with Type II diabetes and renal impairment, who are known to have a high risk for cardiovascular and renal events. Aliskiren was given with optimal cardiovascular treatment, including an ACE inhibitor or ARB. After 18-24 months of concurrent therapy with aliskiren and either an ACE inhibitor or an ARB, there was an increase in non-fatal stroke, renal complications, hyperkalemia, and hypotension.(1,2)

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)

Agents That Affect Catecholamines/Iobenguane I 131

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

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Calcium Channel Blockers/Dantrolene

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

MECHANISM OF ACTION: The exact mechanism is unknown. Dantrolene may decrease the release of calcium from the sarcoplasmic reticulum, resulting in additive or synergistic effects with calcium channel blockers.(1)

CLINICAL EFFECTS: Concurrent use of dantrolene and calcium channel blockers may result in cardiogenic shock.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US, UK, and Australian manufacturers of dantrolene state that concurrent use with calcium channel blockers during the management of malignant hyperthermia crisis is not recommended.(2-4) The Australian and UK manufacturers of diltiazem state that concurrent use of dantrolene infusion with calcium channel blockers is contraindicated.(5-6)

DISCUSSION: Cardiogenic shock in patients treated simultaneously with verapamil and dantrolene is rare but has been reported.(2-4,7) Concurrent use of dantrolene and verapamil in swine has been reported to result in cardiogenic shock and hyperkalemia.(8) In dogs, the combination has been reported to cause hyperkalemia.(9) The combination of diltiazem and dantrolene has been reported to cause adverse cardiovascular effects in swine.(10) A study in swine showed no adverse effects from the combination of dantrolene and nifedipine(10) and one patient who experience cardiogenic shock with dantrolene and verapamil had no adverse effects with the combination of dantrolene and nifedipine;(7) however, the US manufacturer cannot endorse the safety of the combination.(2)

Selected Calcium Channel Blockers/Rifamycins

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

MECHANISM OF ACTION: Multiple mechanisms appear to be involved. Rifampin may increase the hepatic metabolism of the calcium channel blockers, increase first-pass hepatic metabolism of oral calcium channel blockers, and decrease the protein binding of calcium channel blockers.(1-8)

CLINICAL EFFECTS: Concurrent use of rifampin may decrease levels and effectiveness of the calcium channel blocker.(1-8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Observe the patient for a decrease in the therapeutic effects of the calcium channel blocker if rifampin is initiated. The dose of the calcium channel blocker may need to be adjusted if rifampin is initiated or discontinued.(1-7) The US manufacturer of diltiazem states that concurrent use should be avoided.(2) The manufacturer of lercanidipine states that concurrent use is not recommended.(10)

DISCUSSION: In healthy subjects, pretreatment with rifampin (600 mg daily) reduced the concentration of a single dose of isradipine (5 mg) below a detectable level. The study concluded that the concentrations and effects of isradipine may be either reduced or absent as a result of increased isradipine metabolism.(1) Concurrent administration of rifampin has been shown to lower diltiazem levels below detectable limits.(2) In a study in 5 healthy subjects, pretreatment with rifampin (6 days) decreased the area-under-curve (AUC) of a single oral dose of nilvadipine (4 mg) by 96.5%. Pretreatment with rifampin abolished nilvadipine-induced hypotensive effects and tachycardia.(3) A study in six subjects examined the effects of pretreatment with rifampin (600 mg daily for 15 days) on single doses of verapamil (10 mg intravenously or 120 mg orally). Rifampin significantly decreased the maximum concentration (Cmax) and AUC of oral verapamil and resulted in no changes in the P-R interval. There were small decreases in the AUC of intravenous verapamil.(4) In a study in 8 male subjects, pretreatment with rifampin (600 mg daily for 15 days) increased the systemic clearance of S-verapamil by 1.3-fold and the apparent oral-clearance of S-verapamil by 32-fold. The bioavailability of S-verapamil decreased 25-fold. The effect of oral verapamil on AV conduction was almost abolished. No significant changes were noted for intravenous administration of verapamil.(5) In a study in 16 hypertensive chronic kidney disease patients, amlodipine levels decreased an average of 82% after initiation of rifampin. In eight of the 16 patients, the levels were undetectable.(9) There have been case reports of decreased effectiveness of barnidipine,(6) manidipine,(6) nisoldipine,(6) and verapamil(7,8) during concurrent rifampin therapy.

Selected Nephrotoxic Agents/Colistimethate

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

MECHANISM OF ACTION: Colistimethate can cause nephrotoxicity.(1,2) Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1) It is suspected that cephalothin interferes with the excretion of colistimethate resulting in enhanced nephrotoxicity.(2,3)

CLINICAL EFFECTS: Concurrent use of colistimethate with other nephrotoxic agents may result in additive nephrotoxic effects.

PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses of colistimethate, longer treatment duration, hypovolemia, and critical illness.

PATIENT MANAGEMENT: Concurrent use of potentially nephrotoxic agents with colistimethate should be avoided.(1,2) If concurrent use is necessary, it should be undertaken with great caution.(1)

DISCUSSION: In a case control study of 42 patients on intravenous colistimethate sodium, NSAIDs were identified as an independent risk factor for nephrotoxicity (OR 40.105, p=0.044).(4) In 4 case reports, patients developed elevated serum creatinine and blood urea nitrogen following concurrent colistimethate and cephalothin (3 patients) or when colistimethate followed cephalothin therapy (1 patient).(3) A literature review found that individual nephrotoxic agents, including aminoglycosides, vancomycin, amphotericin, IV contrast, diuretics, ACE inhibitors, ARBs, NSAIDs, and calcineurin inhibitors, were not consistently associated with additive nephrotoxicity when used with colistimethate. However, when multiple agents (at least 2 additional potential nephrotoxins) were used concurrently, there was a significant correlation to colistimethate nephrotoxicity.(5)

Weak Cyp3a4 Inhibitors/Eliglustat

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP2D6, eliglustat metabolism can be further inhibited.(1)

CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP3A4 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1)

PREDISPOSING FACTORS: If the patient is also taking an inhibitor of CYP2D6, is a poor metabolizer of CYP2D6, and/or has hepatic impairment, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The concurrent use of eliglustat with weak inhibitors of CYP3A4 in poor metabolizers of CYP2D6 should be avoided.(1) The dosage of eliglustat with weak inhibitors of CYP3A4 in extensive metabolizers of CYP2D6 with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(3)

DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 4-fold and 4.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and 5.4-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, vonoprazan, and ziftomenib.(4,5)

Weak Cyp3a4 Inhibitors/Lomitapide

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of lomitapide.(1) Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Thus even weak CYP3A4 inhibitors may affect lomitapide exposure (AUC, area-under-curve).

CLINICAL EFFECTS: Concurrent use of a weak inhibitor of CYP3A4 may result in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1)

PATIENT MANAGEMENT: When initiating lomitapide in patients taking a stable dose of a weak CYP3A4 inhibitor, follow the recommended dose and titration schedule per labeling. When initiating a weak CYP3A4 inhibitor in patients taking lomitapide, decrease the dose of lomitapide by 50%. The maximum recommended lomitapide dose with concurrent weak CYP3A4 inhibitors should be: -Adults (age 18 years and older): 30 mg daily, -Age group 11 to 17 years: 20 mg daily, -Age group 2 to 10 years: 10 mg daily. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Based upon interactions with stronger inhibitors, weak inhibitors of CYP3A4 are predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1) Weak CYP3A4 inhibitors linked to this interaction include: amiodarone, amlodipine, anamorelin, asciminib, atorvastatin, avapritinib, azithromycin, Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab, camizestrant, cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin, chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant, delavirdine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, sevabertinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, ziftomenib, and zileuton.(1-3)

Weak Cyp3a4 Inhibitors/Pimozide

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of pimozide.(1,2)

CLINICAL EFFECTS: Concurrent use with weak CYP3A4 inhibitors may increase the levels and effects of pimozide including QTc prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes.(1-2) Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increased systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The US manufacturer of pimozide states that concomitant treatment with strong CYP3A4 inhibitors is contraindicated and treatment with less potent inhibitors of CYP3A4 should also be avoided.(1) The UK manufacturer of pimozide contraindicates concomitant use of pimozide with CYP3A4 inhibitors and CYP2D6 inhibitors, stating that inhibition of either or both CYP3A4 and CYP2D6 may result in the elevation of pimozide blood concentration and increase the possibility of QT-prolongation.(2) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(5) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 or CYP2D6 inhibitors if possible. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Pimozide is metabolized at CYP3A.(1,5) Elevated levels of pimozide may prolong the QTc interval resulting in life-threatening ventricular arrhythmias.(1) Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have been reported in patients taking pimozide in combination with itraconazole and/or other CYP3A4 inhibitors.(1,2) Weak CYP3A4 inhibitors include: amlodipine, asciminib, avapritinib, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cimetidine, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fostamatinib, ginkgo, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, marijuana, olaparib, palbociclib, peppermint, piperine, pirtobrutinib, propiverine, ranitidine, resveratrol, scutellarin, sevabertinib, simeprevir, sitaxsentan, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(7,8)

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

Ace Inhibitors/Acemetacin; Proglumetacin; Salsalate

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

MECHANISM OF ACTION: NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and decreased renal blood flow. ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate.

CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy.

DISCUSSION: Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Ace Inhibitors/Azathioprine

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

MECHANISM OF ACTION: The exact mechanism is unknown. Azathioprine-induced impairment of hematopoiesis and ACE inhibitor-induced decreases in erythropoietin may result in additive effects on bone marrow.(1,2)

CLINICAL EFFECTS: The concurrent use of azathioprine and an ACE inhibitor may result in anemia or leucopenia.(1-6) ACE inhibitors have been used to correct post-transplantation erythrocytosis in patients who also received azathioprine.(7)

PREDISPOSING FACTORS: Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency.(8)

PATIENT MANAGEMENT: Patients receiving concurrent therapy with azathioprine and an ACE inhibitor should be closely monitored for hematological changes. One of the agents may need to be discontinued.

DISCUSSION: In a study in 15 kidney-transplant patients receiving azathioprine, enalapril and captopril were replaced by nifedipine or clonidine. Hematocrit and hemoglobin levels increased from 37.5% to 39.7% and from 12.8 g/dl to 13.5 g/dl, respectively,10 to 12 weeks after ACE inhibitor withdrawal. Reticulocytes and erythropoietin concentrations rose from 14.1/1000 to 20.6/1000 and from 14.3 mU/ml to 29.3m U/ml, respectively. There were no changes in azathioprine levels.(1) A retrospective review compared azathioprine-treated patients to patients receiving azathioprine and ACE inhibitors. Hematocrit, hemoglobin, and haptoglobin levels were significantly lower in the group receiving ACE inhibitors, 19.7%, 17.2%, and 45%, respectively.(2) Three case reports document the development of leucopenia during the concurrent administration of captopril and azathioprine.(3-5) Another case report documented the development of anemia with concurrent enalapril and azathioprine.(6) Enalapril has been used to treat post-renal transplant erythrocytosis in patients receiving azathioprine.(7)

Ace Inhibitors/Dipeptidyl Peptidase-Iv Inhibitors

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

MECHANISM OF ACTION: Bradykinin can cause vasodilation and increase vascular permeability both directly and by stimulating release of substance P, which also increases vascular permeability.(1) Bradykinin is primarily metabolized by angiotensin-1 converting enzyme (ACE). If ACE is inhibited by ACE inhibitors, other metabolic enzymes become more significant in bradykinin metabolism, including dipeptidyl peptidase-IV (DPP-IV). DPP-IV inhibitors can inhibit both bradykinin and substance P metabolism.(2)

CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk.(1-3)

PREDISPOSING FACTORS: History of previous angioedema.

PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and DPP-IV inhibitor. Consider switching the patient to an angiotensin receptor blocker or a different anti-diabetic medication. Use caution in patients receiving concurrent therapy.(3) Monitor closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately.

DISCUSSION: A pre-marketing surveillance compared incidence of angioedema in patients on vildagliptin versus a comparator. In all patients combined regardless of ACE inhibitor therapy, there was no association between vildagliptin and angioedema. However among patients taking an ACE inhibitor, vildagliptin was associated with an increased risk of angioedema (odds ratio 9.29 (95% CI 1.22-70.70) from pooled data; odds ratio of 4.57 (95% CI 1.57-13.28) in the meta-analysis). This interaction may be dose-related.(4) In a pooled analysis of data from 19 clinical trials of patients on sitagliptin versus a comparator, there was no difference in the incidence of angioedema between patients on ACE inhibitors and sitagliptin compared to patients on ACE inhibitors alone or patients not on ACE inhibitors.(5) However, events were not adjudicated and encompassed urticaria, anaphylaxis, and hypersensitivity reactions, which may have confounded the results.(6) A disproportionality analysis of the WHO pharmacovigilance database found 340,686 reports of bradykinin-mediated angioedema. Of those, 345 reports involved patients on concomitant ACE inhibitor and DPP-IV inhibitor, with a reporting odds ratio of 42.77 (95% CI 36.93-49.53). There was no association between use of a DPP-IV inhibitor without an ACE inhibitor and angioedema.(7)

Ace Inhibitors/High-Dose Aspirin

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

MECHANISM OF ACTION: NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and decreased renal blood flow. ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate.

CLINICAL EFFECTS: Concurrent use of aspirin may result in decreased antihypertensive effects of the ACE inhibitor. Concurrent use of ACE inhibitors with aspirin and diuretics may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and use of diuretics can lead to hypovolemia and increased risk of AKI.

PATIENT MANAGEMENT: Monitor patients receiving doses of aspirin higher than 150 mg daily for decreased antihypertensive effects of their ACE inhibitor. The use of alternative agents may need to be considered. Concurrent use of ACE inhibitors with aspirin and diuretics should be used with caution and monitored for signs of AKI.

DISCUSSION: Several studies have documented decreased effectiveness of various ACE inhibitors, including captopril, enalapril, and lisinopril following the addition of aspirin therapy. Conflicting evidence exists on the use of small (less than 150 mg) daily doses of aspirin with ACE inhibitors, although some guidelines still suggest they may be beneficial. In a population based cohort study, the concurrent use of NSAIDs with renin-angiotensin system (RAS) inhibitors in 5,710 hypertensive patients stabilized on antihypertensive therapy required hypertension treatment intensification. Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95% CI 1.05-1.71] for NSAIDs in general, 1.79 (95% CI 1.15-2.78) for diclofenac and 2.02 (95% CI 1.09-3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACE inhibitors; HR 4.09, 95% CI 2.02-8.27) or angiotensin receptor blockers (ARBs; HR 3.62, 95% CI 1.80-7.31), but not with other antihypertensive drugs. In a computational study, the risk of AKI using triple therapy (combination of 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.(20,21) 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).(22) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Ace Inhibitors/Hymenoptera Venom Immunotherapy

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

MECHANISM OF ACTION: Angiotensin converting enzyme (ACE) inhibitors block the conversion of angiotensin I to angiotensin II, resulting in vasodilation and disrupting the compensatory response during anaphylaxis. Concurrent use of ACE inhibitors may increase the risk and severity of an anaphylactoid reaction to Hymenoptera venom immunotherapy.(1-15)

CLINICAL EFFECTS: Angiotensin converting enzyme (ACE) inhibitors may increase the risk and severity of an anaphylactoid reaction to Hymenoptera venom immunotherapy.(1-15)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Administration of Hymenoptera venom immunotherapy in patients on angiotensin converting enzyme (ACE) inhibitors should be approached with caution. In patients taking ACE inhibitors, consider temporarily withholding ACE inhibitor therapy prior to each immunotherapy procedure. If patients cannot safely discontinue ACE inhibitors, monitor patients closely for signs of an anaphylactoid reaction.(1-15)

DISCUSSION: Patients on angiotensin converting enzyme (ACE) inhibitors may be at increased risk of an anaphylactoid reaction to Hymenoptera venom immunotherapy. Clinical studies and guideline recommendations for concurrent use of ACE inhibitors and Hymenoptera venom immunotherapy range from use with caution to a relative contraindication. Patients should be informed of the potential risk of the possible interaction.(1-22)

Ace Inhibitors/Racecadotril

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

MECHANISM OF ACTION: Bradykinin can cause vasodilation and increase vascular permeability both directly and by stimulating release of substance P, which also increases vascular permeability.(1) Bradykinin is primarily metabolized by angiotensin-1 converting enzyme (ACE). If ACE is inhibited by ACE inhibitors, other metabolic enzymes become more significant in bradykinin metabolism, including neutral endopeptidase (NEP). Racecadotril inhibits NEP which is involved in the degradation of bradykinin.(2)

CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk.(1)

PREDISPOSING FACTORS: History of previous angioedema.

PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and racecadotril.(1) Consider switching the patient to an angiotensin receptor blocker. Use caution in patients receiving concurrent therapy.(3) Monitor closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately.

DISCUSSION: Angioedema has been reported with racecadotril. Concurrent use of racecadotril and an ACE inhibitor may increase the risk of angioedema. A review of the French national pharmacovigilance database found 11 reports of angioedema in patients concomitantly taking an ACE inhibitor and racecadotril. In 9 cases, the temporal relationship between onset of drug combination and onset of angioedema was highly suggestive of a causal link.(3)

Ace Inhibitors/Selected Nsaids; Salicylates

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

MECHANISM OF ACTION: NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and decreased renal blood flow. ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate.

CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. Concurrent use of ACE inhibitors with NSAIDs and diuretics may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individuals susceptibility to AKI.

PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy. Concurrent use of ACE inhibitors with NSAIDs and diuretics should be used with caution and monitored closely for signs of AKI.

DISCUSSION: In a computational study, the risk of AKI using triple therapy (combination of 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.(30,31) 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).(32) Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

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)

Amlodipine/Apalutamide; Carbamazepine

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

MECHANISM OF ACTION: Concurrent use of apalutamide or carbamazepine may induce the CYP3A4 mediated metabolism of amlodipine.(1-3)

CLINICAL EFFECTS: Concurrent use of apalutamide or carbamazepine may decrease levels and effectiveness of amlodipine.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of apalutamide recommends substituting amlodipine with a drug not metabolized by CYP3A4 when possible. If concurrent therapy with apalutamide or carbamazepine is necessary, monitor the patient for a decrease in the therapeutic effects of amlodipine. The dose of amlodipine may need to be adjusted.(1-3)

DISCUSSION: Apalutamide is a strong inducer of CYP3A4. Amlodipine is metabolized by CYP3A4 and has been shown to be affected by other strong CYP3A4 inducers. In a study in 16 hypertensive chronic kidney disease patients, amlodipine levels decreased an average of 82% after initiation of rifampin. In eight of the 16 patients, the levels were undetectable.(4) A case report describes a 53-year-old women with schizophrenia and hypertension who was stable on paliperidone and amlodipine 5 mg daily. Upon carbamazepine initiation, amlodipine levels decreased by 68%, and blood pressure increased from a baseline of 138/91 to 160/103. Blood pressure normalized after discontinuation of carbamazepine.(5)

Amlodipine/Simvastatin (<=20 Mg)

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

MECHANISM OF ACTION: Amlodipine may inhibit the metabolism of simvastatin by CYP3A4.(1-7) Levamlodipine is the active isomer of amlodipine.(8)

CLINICAL EFFECTS: Concurrent amlodipine may result in elevated levels of simvastatin,(1-7) which may result in myopathy and rhabdomyolysis.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Do not exceed a dosage of 20 mg daily of simvastatin in patients receiving concurrent therapy with amlodipine.(1-4) Consider separating the administration times of amlodipine and simvastatin in patients receiving concurrent therapy with amlodipine and simvastatin doses of 20 mg or less.(5)

DISCUSSION: In a study in 8 patients with hypercholesterolemia and hypertension, 4 weeks of concurrent administration of amlodipine (5 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of simvastatin (5 mg daily) by 43% and 28%, respectively. There were no changes in the lipid-lowering affects of simvastatin.(6) In a study in 17 subjects, administration of amlodipine (5 mg daily) 4 hours after simvastatin (5 mg daily) resulted in Cmax and AUC values of simvastatin that were 63.2% and 66.0%, respectively, of values obtained with simultaneous dosing.(5) Acute renal failure and rhabdomyolysis was reported in patient maintained on amlodipine and alprazolam two days after beginning the maximal dose of simvastatin.(7)

Amlodipine; Levamlodipine/Slt Strong Cyp3a4 Inhibit

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

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the first-pass and elimination metabolism of calcium channel blockers by CYP3A4.

CLINICAL EFFECTS: The concurrent use of strong CYP3A4 inhibitors with calcium channel blockers metabolized by CYP3A4 may result in elevated levels of the calcium channel blocker and risk of adverse effects, including hypotension and bradycardia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with calcium channel blockers should be approached with caution. When these agents are used concurrently, the dose of the calcium channel blocker may need to be adjusted or an alternative agent considered. Monitor patients for increased calcium channel blocker effects. If the strong CYP3A4 inhibitor is discontinued, the dose of the calcium channel blocker may need to be increased and patients should be observed for decreased effects.

DISCUSSION: Coadministration of a 180 mg dose of diltiazem (moderate CYP3A4 inhibitor) with 5 mg amlodipine resulted in a 60% increase in amlodipine systemic exposure. Strong inhibitor of CYP3A4 may increase plasma concentrations of amlodipine to a greater extent.(1) In a study in 19 healthy subjects, telaprevir (750 mg every 8 hours for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of amlodipine (5mg) by 1.27-fold and 2.79-fold, respectively.(3) Strong CYP3A4 inhibitors include: adagrasib, ceritinib, clarithromycin, cobicistat, ensitrelvir, fluconazole, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, relacorilant, ribociclib, saquinavir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5)

Calcium Channel Blockers/Cyclosporine

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

MECHANISM OF ACTION: Calcium channel blockers may inhibit the metabolism of cyclosporine by CYP3A4.

CLINICAL EFFECTS: Concurrent use of calcium channel blockers may result in elevated levels of and toxicity from cyclosporine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor cyclosporine levels when initiating or discontinuing calcium channel blockers.

DISCUSSION: Concurrent administration of cyclosporine and amlodipine, diltiazem, nicardipine, or verapamil has caused elevated cyclosporine levels. Renal toxicity was seen in some cases. Upon discontinuation of the calcium channel blocker, cyclosporine concentrations have returned to baseline levels. With concurrent diltiazem administration, cyclosporine dosage decreases of 15% to 48% were required. A prospective study in 11 renal transplant patients showed a 40% increase in trough cyclosporine levels when given concomitantly with amlodipine.(29)

Calcium Channel Blockers/Selected Hepatitis C Agents

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

MECHANISM OF ACTION: Boceprevir(1), ombitasvir-paritaprevir-ritonavir,(2) or telaprevir(3) may inhibit the metabolism of calcium channel blockers by CYP3A4.

CLINICAL EFFECTS: Concurrent use of boceprevir, ombitasvir-paritaprevir-ritonavir, or telaprevir may result in elevated levels of and toxicity from calcium channel blockers.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with either boceprevir, ombitasvir-paritaprevir-ritonavir, or telaprevir and amlodipine for increased calcium channel blocker effects. The dosage of the calcium channel blocker may need to be adjusted(1,3) or an alternative agent considered.(1,3) The US manufacturer of ombitasvir-paritaprevir-ritonavir states that when administered concomitantly with amlodipine the dose of amlodipine should be decreased by at least 50%. Monitor patients for edema and/or signs and symptoms of hypotension. If these events occur, consider further dose reduction of amlodipine or switching to an alternative calcium channel blocker.

DISCUSSION: In a study in 19 healthy subjects, telaprevir (750 mg every 8 hours for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of amlodipine (5mg) by 1.27-fold and 2.79-fold, respectively.(3,4) In an interaction study, 26 healthy subjects were given ombitasvir-paritaprevir-ritonavir and dasabuvir for 24 days. A single dose of amlodipine 5 mg was given on day 1 and 14 of therapy. Amlodipine AUC increased 2.1-fold and the half-life increased from 42 (+ or - 6.7) hours to 104 (+ or - 18) hours.(5)

Selected Ace Inhibitors/Indomethacin

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

MECHANISM OF ACTION: NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and decreased renal blood flow. ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate.

CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. Concurrent use of ACE inhibitors with NSAIDs and diuretics may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individuals susceptibility to AKI.

PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy.

DISCUSSION: Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. In a computational study, the risk of AKI using triple therapy (combination of 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.(30,31) 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).(32) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Selected Ace Inhibitors/Potassium Sparing Diuretics

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

MECHANISM OF ACTION: ACE inhibitors may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium sparing diuretics with an ACE inhibitor 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 ACE inhibitors. In all patients taking eplerenone who start taking an ACE inhibitor, 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 concomitant 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 ACE inhibitors with potassium sparing diuretics. Selected ACE inhibitors linked to this monograph include: benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.

Selected Ace Inhibitors/Potassium Supplements

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

MECHANISM OF ACTION: ACE inhibitors may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium supplements with ACE inhibitors 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 ACE inhibitors.

DISCUSSION: Several studies have indicated that serum potassium levels increase when ACE inhibitors 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 ACE inhibitors. Selected ACE inhibitors linked to this monograph include: alacepril, cilazapril, delapril, imidapril, perindopril, spirapril, temocapril, and zofenopril.

Selected Ace Inhibitors/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 ACE inhibitors 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)

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 Calcium Channel Blockers/Nirmatrelvir-Ritonavir

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

MECHANISM OF ACTION: Nirmatrelvir-ritonavir may inhibit the metabolism of calcium channel blockers by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of nirmatrelvir-ritonavir may result in elevated levels of and toxicity from calcium channel blockers.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of nirmatrelvir-ritonavir and selected calcium channel blockers should be approached with caution. Monitor patients receiving concurrent therapy with nirmatrelvir-ritonavir and either amlodipine, diltiazem, felodipine, nicardipine, nifedipine, or verapamil for increased calcium channel blocker effects. The dosage of the calcium channel blocker may need to be adjusted.(1,2) The Journal of American College of Cardiology recommends a 50% reduction in the dose amlodipine for 8 days with the initiation of nirmatrelvir-ritonavir. Close monitoring of blood pressure and dose reduction or temporary discontinuation of calcium channel blockers may be needed. Resume calcium channel blockers 3 days after the last dose of nirmatrelvir-ritonavir.(3)

DISCUSSION: Nirmatrelvir-ritonavir is a strong CYP3A4 inhibitor and may increase the levels of calcium channel blockers that are CYP3A4 substrates.(1,2) In a case report of a 80-year old female on verapamil, on day 2 of concurrent nirmatrelvir-ritonavir the patient presented to the hospital with symptomatic bradycardia (heart rate of 28 beats per minute and blood pressure of 58/35 mmHg) requiring hospitalization, medical management, and a temporary transvenous pacer.(4)

Selected Calcium Channel Blockers/Tacrolimus

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

MECHANISM OF ACTION: Some calcium channel blockers may inhibit the metabolism of tacrolimus by CYP3A4.(1-13)

CLINICAL EFFECTS: Concurrent use of calcium channel blockers may result in elevated levels of and side effects from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1-13)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).

PATIENT MANAGEMENT: Patients maintained on tacrolimus should be closely monitored if calcium channel blockers such as amlodipine, diltiazem, felodipine, nifedipine, or verapamil are initiated or discontinued. The dosage of tacrolimus may need to be adjusted or the calcium channel blocker may need to be discontinued. When concurrent therapy of selected calcium channel blockers and tacrolimus is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: A study of 9 healthy volunteers who are CYP3A5 expressers found that concomitant tacrolimus and amlodipine resulted in increased tacrolimus AUC by 2.44-fold and 4.1-fold in a single-dose and a 7-day multi-dose study, respectively, compared to tacrolimus alone. No interaction was observed in CYP3A5 non-expressers.(2) However, a case report of a 4-year-old renal transplant patient who is a CYP3A5 non-expresser on tacrolimus and started on amlodipine described increased tacrolimus trough level and AUC from 3.7 to 12.2 ng/mL and 211 to 638 h/ng/mL, respectively.(3) A non-randomized study in 2 liver and 2 renal transplant recipients examined the effects of diltiazem on tacrolimus. In the 2 kidney recipients, concurrent diltiazem at a dosage of 20 mg daily increased tacrolimus AUC by 26% and by 67%. Diltiazem at a dosage of 180 mg increased tacrolimus AUC by 48% and by 177%. In the 2 liver recipients, no tacrolimus increases were seen until diltiazem dosage reached 60 mg daily. One subject received 120 mg of diltiazem daily and tacrolimus AUC was increased by 18%. The other subject received 180 mg diltiazem daily and tacrolimus AUC increased 22%.(4) There is one case report of elevated tacrolimus levels and toxicity in a liver transplant patient 3 days after the addition of diltiazem to his regimen.(5) There is one case report of elevated tacrolimus levels in a renal transplant patient.(6) In contrast, a retrospective review of renal transplant patients found no difference in tacrolimus-related side effects or tacrolimus exposure in patients treated with diltiazem versus those not treated with diltiazem.(7) There is one report of increased tacrolimus levels with concurrent felodipine in a renal transplant patient.(8) A retrospective review examined the effects of nifedipine on tacrolimus dosing requirements in renal transplant patients. In patients who received concurrent nifedipine (n=22), tacrolimus daily dosing requirements were 26%, 29%, and 38% lower at 3, 6, and 12 months post-transplant when compared to patients not taking nifedipine (n=28).(9) In a study of liver transplant patients, nifedipine improved kidney function as indicated by lowering of serum creatinine levels at 6 and 12 months.(10) In vitro studies in human tissue found that tacrolimus metabolism was inhibited by nifedipine and verapamil.(12,13)

Slt Calcium Channel Blockers/Atazanavir;Darunavir;Fosampren

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

MECHANISM OF ACTION: Atazanavir, darunavir, and fosamprenavir may inhibit the CYP3A4-mediated metabolism of calcium channel blockers.(1-5)

CLINICAL EFFECTS: Concurrent use of atazanavir, darunavir, or fosamprenavir may result in increased levels of calcium channel blockers. The combination of atazanavir with non-dihydropyridines may result in an additive effect on the PR interval.(1-2,6-7)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US Department of Health and Human Services HIV guidelines recommend that concurrent use of calcium channel blockers with protease inhibitors be monitored closely. The dose of the calcium channel blocker should be titrated to clinical response and adverse events.(5) Additional recommendations apply to patients on atazanavir. EKG monitoring is recommended for patients on concurrent therapy with calcium channel blockers. A dose reduction of diltiazem by 50% should be considered for patients starting atazanavir.(1,2,5)

DISCUSSION: In a study in 28 subjects, concurrent atazanavir (400 mg daily) with diltiazem (180 mg daily) increased the diltiazem area-under-curve (AUC) and maximum concentration (Cmax) by 225% and 98%, respectively.(1,2) Diltiazem minimum concentration (Cmin) increased by 242%. The Cmax, AUC, and Cmin of desacetyl-diltiazem increased by 272%, 265%, and 221%, respectively. There were no significant effects on atazanavir levels.(1)

Slt Moderate And Weak Cyp3a4 Inhibit/Sirolimus Protein-Bound

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

MECHANISM OF ACTION: Moderate and weak CYP3A4 inhibitors may inhibit the metabolism of sirolimus by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of moderate or weak CYP3A4 inhibitors may result in elevated levels of and side effects from sirolimus.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: In an open, randomized, cross-over trial in 18 healthy subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10 mg) increased sirolimus area-under-curve (AUC) and maximum concentration (Cmax) by 60% and by 43%, respectively. Sirolimus apparent oral clearance and volume of distribution decreased by 38% and 45%, respectively. There were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2) In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold and 2.3-fold, respectively. The AUC and Cmax of the active S-enantiomer of verapamil each increased by 1.5-fold. Verapamil time to Cmax (Tmax) was increased by 1.2 hours.(2) Moderate and weak CYP3A4 inhibitors linked to this monograph include: amlodipine, anamorelin, aprepitant, avacopan, azithromycin, berberine, berotralstat, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, crizotinib, daclatasvir, daridorexant, delavirdine, diltiazem, diosmin, elinzanetant, estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, gepotidacin, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, oral lefamulin, lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone, lurasidone, mavorixafor, netupitant, nicardipine, omeprazole, osilodrostat, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, rimegepant, roxithromycin, scutellarin, sevabertinib, simeprevir, sitaxsentan, stiripentol, ticagrelor, tofisopam, tolvaptan, trofinetide, vonoprazan, and voxelotor.(3,4)

Weak Cyp3a4 Inhibitors/Lemborexant (<= 5 Mg)

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

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(1,3)

Weak Cyp3a4 Inhibitors/Mavacamten

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

MECHANISM OF ACTION: Weak CYP3A4 inhibitors may decrease the metabolism of mavacamten.(1)

CLINICAL EFFECTS: Concurrent use of weak CYP3A4 inhibitors may increase the plasma levels and the incidence and severity of adverse reactions of mavacamten.(1)

PREDISPOSING FACTORS: CYP2C19 poor metabolizers may experience an increased incidence or severity of adverse effects.(1)

PATIENT MANAGEMENT: The UK manufacturer of mavacamten states no dose adjustment is necessary when starting mavacamten in patients on weak CYP3A4 inhibitors or in intermediate, normal, rapid, or ultra-rapid CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor. In poor CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor, reduce mavacamten 5 mg to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks. If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of 2.5 mg daily.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: In a PBPK model, concomitant use of mavacamten (15 mg daily) with cimetidine 400 mg twice daily, a weak CYP3A4 inhibitor, was predicted to increase mavacamten area-under-curve (AUC) by 6% and maximum concentration (Cmax) by 4% in poor CYP2C19 metabolizers and by 3% and 2%, respectively, in both intermediate and normal CYP2C19 metabolizers.(3) Weak CYP3A4 inhibitors include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol, clotrimazole, cranberry, cyclosporine, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, istradefylline, ivacaftor, lacidipine, lapatinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, pazopanib, peppermint oil, propiverine, propofol, ranitidine, resveratrol, roxithromycin, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, and viloxazine. (4,5)

Weak Cyp3a4 Inhibitors/Ubrogepant (<= 50 Mg)

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(3,4)

Amlodipine is contraindicated in patients with known hypersensitivity to the drug.

*Known hypersensitivity (e.g., history of angioedema) to perindopril, other angiotensin-converting enzyme (ACE) inhibitors, or any ingredient in the formulation.

*History of hereditary or idiopathic angioedema.

*Concomitant aliskiren therapy in patients with diabetes mellitus.

*Concomitant use (within 36 hours) of a neprilysin inhibitor (e.g., sacubitril).

• Angioedema
• Hereditary angioedema
• Pregnancy

• Disease of liver
• Hyperkalemia
• Hypotension
• Neutropenic disorder
• Severe aortic valve stenosis

• Bone marrow depression
• Disease of liver
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Renal artery stenosis

Adverse effects reported in 1% or more of patients receiving amlodipine include dose-related edema, dizziness, flushing, and palpitations; fatigue, nausea, abdominal pain, and somnolence also reported. Adverse effects reported in the clinical trial in pediatric patients with hypertension were similar to those that have been reported in adults.

Adverse effects occurring in patients receiving perindopril for hypertension at an incidence >=5% included cough, dizziness, and back pain.

Adverse effects occurring in patients receiving perindopril for stable coronary artery disease leading to treatment discontinuation were cough, drug intolerance, and hypotension.

Less Frequent

• Hypotension
• Increased alanine transaminase

Rare or Very Rare

• Abnormal hepatic function tests
• Acute myocardial infarction
• Acute pancreatitis
• Acute renal failure
• Agranulocytosis
• Anaphylaxis
• Anemia
• Angioedema
• Angioedema
• Aplastic anemia
• Atrial fibrillation
• Bradycardia
• Depersonalization
• Depression
• Eosinophilia
• Eosinophilic pneumonia
• Erythema multiforme
• Exfoliative dermatitis
• Extrapyramidal disease
• Head and neck angioedema
• Hemolytic anemia
• Hepatic failure
• Hepatitis
• Hyperkalemia
• Hyponatremia
• Hypotension
• Increased aspartate transaminase
• Intestinal angioedema
• Jaundice
• Leukopenia
• Nephritis
• Neutropenic disorder
• Pancreatitis
• Pancytopenia
• Progressive angina pectoris
• Pulmonary edema
• Purpura
• Thrombocytopenic disorder
• Thrombocytopenic disorder
• Vasculitis
• Ventricular tachycardia

More Frequent

• Acute abdominal pain
• Back pain
• Cough
• Dizziness
• Drowsy
• Edema
• Headache disorder
• Nausea
• Peripheral edema

Less Frequent

• Arthralgia
• Dizziness
• Fatigue
• Fever
• Flushing
• General weakness
• Headache disorder
• Myalgia
• Palpitations
• Skin rash

Rare or Very Rare

• Abnormal sexual function
• Acute abdominal pain
• Anorexia
• Arthralgia
• Back pain
• Chest pain
• Chills
• Conjunctivitis
• Constipation
• Cramps
• Diarrhea
• Dream disorder
• Drug-induced hot flash
• Dysphagia
• Dyspnea
• Epistaxis
• Flatulence
• General weakness
• Gingival hyperplasia
• Gynecomastia
• Hyperglycemia
• Hyperhidrosis
• Hypoesthesia
• Increased urinary frequency
• Insomnia
• Maculopapular rash
• Malaise
• Myalgia
• Nervousness
• Nocturia
• Ocular pain
• Osteoarthritis
• Paresthesia
• Pemphigus
• Peripheral ischemia
• Peripheral neuropathy
• Polydipsia
• Pruritus of skin
• Psoriasis
• Skin rash
• Symptoms of anxiety
• Syncope
• Tachycardia
• Tinnitus
• Tremor
• Vasculitis
• Vertigo
• Visual changes
• Vomiting
• Weight gain
• Weight loss
• Xerostomia

No enhanced messaging available.

Safety and efficacy of amlodipine in children younger than 6 years of age have not been established. Safety and effectiveness of amlodipine (2.5-5 mg daily) for the treatment of pediatric patients 6-17 years of age with hypertension have been established in a trial of 8 weeks' duration.

Safety and efficacy of amlodipine in fixed combination with atorvastatin, benazepril, olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide) have not been established in pediatric patients.

Safety and efficacy of perindopril are not established in pediatric patients.

If oliguria or hypotension occurs in neonates with a history of in utero exposure to perindopril, support blood pressure and renal function; exchange transfusions or dialysis may be required.

The manufacturers state that there are limited data on use of amlodipine in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. There is some data indicating that amlodipine crosses the placenta in measurable quantities in the third trimester of pregnancy.

Hypertension in pregnancy is a major cause of maternal, fetal or neonatal morbidity and mortality. Maternal risks include pre-eclampsia, gestational diabetes, premature delivery, placental abruption, delivery complications (e.g., need for cesarean section, postpartum hemorrhage), stroke, pulmonary edema, thromboembolic events, multiple organ failure (liver, kidney) and disseminated intravascular coagulation. Fetal risks include intrauterine growth restriction, prematurity, and intrauterine death. Neonates may require prolonged high-level care and experience morbidity. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Teratogenicity or other embryo-fetal toxicity was not observed when pregnant rats and rabbits were treated orally with a different salt form of amlodipine (amlodipine maleate) at doses up to 10 mg/kg per day (approximately 10 and 20 times the maximum recommended human dose (MRHD) based on body surface area, respectively) during their respective periods of major organogenesis. However, when amlodipine maleate at doses up to 10 mg amlodipine/kg per day was administered to rats for 14 days prior to mating and throughout gestation, litter size decreased approximately 50%, and a 5-fold increase in the number of intrauterine deaths was observed at this dose equivalent to 10 times the MDRD. Amlodipine maleate has also been shown to prolong both the gestation period and the duration of labor in rats at this dose.

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. Perindopril crosses the placenta. Radioactivity was detectable in fetuses after administration of 14C-perindopril to pregnant rats.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both the mother and fetus. Verify pregnancy status in females of reproductive potential prior to initiation of perindopril. Discontinue perindopril as soon as possible when pregnancy is detected.

In the rare situation that use of perindopril is deemed necessary, apprise the mother of the risk to the fetus. Perform serial ultrasound examinations to assess the intraamniotic environment. Fetal testing may be appropriate, based on the week of pregnancy; however, oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, discontinue perindopril unless it is considered lifesaving for the mother. Closely observe infants with histories of in utero exposure to perindopril for hypotension, oliguria, and hyperkalemia.

The manufacturer states limited available data from a published clinical lactation study reported that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed; there is no available information on the effects of amlodipine on milk production.

It is not known whether perindopril is secreted in human milk. Milk of lactating rats contained radioactivity following administration of 14C-perindopril.

Because many drugs are secreted in human milk, exercise caution when perindopril is given to breast-feeding mothers.

The elimination of amlodipine may be impaired substantially in geriatric patients, resulting in increased exposure to the drug (AUC increases of 40-60%). For management of hypertension, some manufacturers recommend an initial amlodipine dosage of 2.5 mg once daily for geriatric patients. For management of vasospastic (Prinzmetal variant) angina or chronic stable angina in geriatric patients, an amlodipine dosage of 5 mg daily is recommended; adequate control of angina usually requires a maintenance dosage of 10 mg once daily.

In geriatric patients with hypertension, the recommended initial daily dosage of perindopril erbumine is 4 mg daily, given in 1 or 2 divided doses. Experience is limited with daily dosages above 8 mg; dosages above 8 mg daily require careful titration and close blood pressure monitoring.

In geriatric patients (>70 years) receivingperindopril erbumine for stable coronary artery disease, the recommended dosage is 2 mg once daily in the first week,followed by 4 mg once daily in the second week and 8 mg once daily as the maintenance dosage, if tolerated.

In geriatric patients, amlodipine clearance is decreased and AUC is increased by about 40-60%. Therefore, amlodipine dosage should be selected carefully, usually initiating therapy with dosages at the lower end of the recommended range (i.e., 2.5 mg daily). The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.

Clinical studies of amlodipine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients; however, other clinical experience has not revealed age-related differences in response or tolerance.

Perindopril has been reported to have a somewhat smaller, but not significantly different, effect on blood pressure in those 60 years of age and older than in younger patients. Increased plasma concentrations of perindopril and perindoprilat (active metabolite) have been reported in geriatric patients compared with younger patients. Dizziness and possibly rash may occur more frequently in geriatric patients; monitor for dizziness because of the potential for falls.

In geriatric patients, start perindopril at a low dose and titrate slowly as needed. Experience with perindopril in geriatric patients at daily doses exceeding 8 mg is limited.