Felodipine Er (felodipine)

No dosing information is available for this tab.

Felodipine is administered orally as extended-release tablets. The tablets should be swallowed intact and should not be chewed or crushed. Since peak concentrations of the drug were increased by 60% when felodipine was administered with a high-fat or high-carbohydrate meal and no changes in pharmacokinetics were observed when the drug was administered with a light meal (e.g., orange juice, toast, and cereal), the manufacturer states that felodipine should be taken either without food or with a light meal. However, the bioavailability of felodipine as determined by AUC was not affected when the extended-release tablets containing felodipine were administered with a high-fat or high-carbohydrate meal.

Concomitant administration with grapefruit juice has been shown to increase oral bioavailability of felodipine 2-fold compared with concomitant administration with orange juice or water. Concomitant oral administration of grapefruit juice usually should be avoided since potentially clinically important increases in hemodynamic effects can result.

Store extended-release tablets in a tightly closed container at 20-25degreesC; protect from light.

Felodipine is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.

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

Felodipine;Nisoldipine/Itraconazol;Ketoconazol;Levoketocon

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: Itraconazole(1), ketoconazole(2), and levoketoconazole(3) may inhibit the metabolism of felodipine by CYP3A4. Nisoldipine has a low absolute bioavailability of approximately 5% due to intestinal and hepatic first-pass metabolism by CYP3A4.(4) FDA designates nisoldipine as a CYP3A4 sensitive substrate, i.e. a drug whose plasma area-under-curve (AUC) has been shown to increase 5-fold or more in the presence of a strong inhibitor of CYP3A4.(5) Both itraconazole(1,5-6) and ketoconazole(2,5-6) are strong inhibitors of CYP3A4. In addition, itraconazole has been shown to have negative inotropic effects, which may be additive with those of nisoldipine.(1)

CLINICAL EFFECTS: The concurrent administration of itraconazole or ketoconazole may result in a 6 to 8 fold increase in felodipine AUC(1) or a 10 to 24-fold increase in nisoldipine AUC(1) leading to adverse effects such as severe hypotension or peripheral edema.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of itraconazole(1,7,8), ketoconazole(2,9), or levoketoconazole(3) with felodipine or nisoldipine is contraindicated. The US manufacturer of itraconazole states that concurrent administration with felodipine or nisoldipine is contraindicated during and two weeks after itraconazole treatment.(1) While all dihydropyridine calcium channel blockers are metabolized and could be affected by CYP3A4 inhibitors, nisoldipine and felodipine are particularly sensitive to CYP3A4 inhibition.(6) If ketoconazole or itraconazole therapy is required, it would be prudent to change to a low dose of a different dihydropyridine with careful monitoring for adverse effects.

DISCUSSION: A double-blind, randomized, two-phase crossover study in nine subjects examined the effects of itraconazole on felodipine. The area-under-curve (AUC) and half-life of felodipine increased by 6-fold and 2-fold, respectively, during concurrent itraconazole. In seven of the nine subjects, the maximum concentration (Cmax) of felodipine when administered with placebo was lower than the 32-hour concentration of felodipine when administered with itraconazole. Concurrent use also resulted in significantly greater effects on both blood pressure and heart rate.(10) There are two case reports of patients developing edema following the addition of itraconazole to felodipine therapy. In the second report, the patient was rechallenged with concurrent itraconazole and again developed edema.(11) Concurrent use of itraconazole produces clinically significant increases in nisoldipine levels that cannot be managed by dosage adjustment.(1) A randomized cross-over trial in seven subjects examined the effects of ketoconazole (200 mg daily for 4 days) on nisoldipine (5 mg daily). The concurrent use of ketoconazole increased the nisoldipine AUC and Cmax by 24-fold and 11-fold, respectively. Increases in the M9 nisoldipine metabolite were similar.(12) A study in 14 healthy volunteers with concurrent administration of levoketoconazole (400 mg once daily) with felodipine increased the felodipine AUC and Cmax by 1007.3% and 937.1%.(3)

Selected Cyp3a4 Substrates/Mifepristone

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: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme.(1)

CLINICAL EFFECTS: Lovastatin, simvastatin and CYP3A4 substrates with a narrow therapeutic window such as alprazolam, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, and tacrolimus or CYP3A4 substrates with a high first pass effect such as oral midazolam, sildenafil, and triazolam are particularly susceptible to significant toxicity.(1,2)

PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity. With pimozide, 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.(3)

PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with lovastatin, simvastatin, CYP3A4 substrates with a narrow therapeutic range, or CYP3A4 substrates with a high first pass effect is contraindicated.(1)

DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively.

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

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)

Diltiazem; Felodipine; Verapamil/St. John's Wort

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

MECHANISM OF ACTION: St. John's wort may induce the metabolism of diltiazem, felodipine and verapamil by the CYP3A4.(1-3)

CLINICAL EFFECTS: The concurrent administration of St. John's wort may result in decreased levels and clinical effects of diltiazem, felodipine and verapamil.(1-3)

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

PATIENT MANAGEMENT: Concurrent use is not recommended. Patients receiving both a selected calcium channel blocker and St. John's wort should be alerted to the possibility of decreased effects of the calcium channel blocker.(1) Observe the patient for loss of the therapeutic effect of the calcium channel blocker. The dose of the calcium channel blocker may need to be adjusted if St. John's wort is added to or discontinued from concurrent therapy. St. John's wort may need to be discontinued.

DISCUSSION: One study looked at the effects of St. John's wort on the metabolism of S- and R-verapamil in eight healthy male subjects. The patients underwent jejunal perfusion with verapamil before and after taking St. John's wort (300 mg three times daily) for 14 days. The study concluded that St. John's wort decreased the area-under-curve (AUC) and the maximum plasma concentration (Cmax) of both the S- and R-enantiomers by 80% and 78%, respectively. The induction of first pass verapamil metabolism by St. John's wort was shown to significantly decrease the bioavailability of the medication.(2) St. John's wort has been shown to decrease levels of indinavir in healthy subjects.(3) Because selected calcium channel blockers (diltiazem, felodipine) are metabolized by the same metabolic pathway, the FDA recommends that patients taking these calcium channel blockers be alerted to the possibility of a drug interaction resulting in decreased levels and/or effects of the calcium channel blocker.(1)

Felodipine/Lumacaftor

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

MECHANISM OF ACTION: Lumacaftor, a strong inducer of CYP3A4, may induce the metabolism of felodipine.(1) Felodipine is designated as a sensitive CYP3A4 substrate; strong inducers may decrease exposure (area-under-curve, AUC) by > or = 80%.(2)

CLINICAL EFFECTS: Serum levels and bioavailability of felodipine may be decreased resulting in a decrease or loss of antihypertensive or antianginal effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lumacaftor states concurrent use with sensitive CYP3A4 substrates is not recommended.(1) Consider use of other antihypertensive agents (except nisoldipine, also a sensitive CYP3A4 substrate) when possible. In patients already receiving felodipine when lumacaftor is started, the onset of this interaction may be delayed, and maximal induction effects may not be seen for 2 or more weeks. Monitor antihypertensive response and adjust the dose of felodipine as needed. In patients stabilized on lumacaftor therapy, the addition of felodipine may not be effective for treatment of hypertension or angina.

DISCUSSION: In an interaction study lumacaftor reduced exposure to ivacaftor, another CYP3A4 sensitive substrate, by 80%.(1) A study in healthy subjects compared felodipine exposure in patients receiving felodipine alone or with another strong CYP3A4 inducer (phenytoin). Combination therapy reduced felodipine exposure (area-under-curve) by 94%.(3)

Felodipine/Selected Strong Cyp3a4 Inducers

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

MECHANISM OF ACTION: Felodipine is designated as a sensitive CYP3A4 substrate. Strong CYP3A4 inducers may induce the metabolism of felodipine and decrease exposure (area-under-curve, AUC) by 80% or more.(1-2) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Serum levels and bioavailability of felodipine may be decreased resulting in a decrease or loss of antihypertensive or antianginal effects.

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

PATIENT MANAGEMENT: The US manufacturer of felodipine states that alternative antihypertensive agents should be considered in patients taking anticonvulsants that induce CYP3A4.(1) Although there are no specific recommendations for other strong CYP3A4 inducers, a clinically significant interaction can be expected and a similar approach is reasonable with concurrent use. Monitor antihypertensive response and adjust the dose of felodipine as needed. In patients already receiving felodipine when the CYP3A4 inducer is started, the onset of this interaction may be delayed, and maximal induction effects may not be seen for 2 or more weeks. Monitor antihypertensive response and adjust the dose of felodipine as needed. In patients stabilized on the CYP3A4 inducer therapy, the addition of felodipine may not be effective for treatment of hypertension or angina.

DISCUSSION: A study in healthy subjects compared felodipine exposure in patients receiving felodipine alone or with another strong CYP3A4 inducer (phenytoin). Combination therapy reduced felodipine exposure (area-under-curve, AUC) by 94%.(3) Felodipine levels have been shown to be reduced by 90% in patients taking anticonvulsants such as carbamazepine. Strong CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin and primidone.(2,4)

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 Calcium Channel Blockers/Selected Macrolides

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

MECHANISM OF ACTION: Some macrolides may inhibit metabolism of calcium channel blockers.(1) In some patients, calcium channel blockers may inhibit the metabolism of the macrolide. Some macrolides have been associated with cardiac arrhythmias, including torsades de pointes.(2)

CLINICAL EFFECTS: In some patients, concurrent use may result in elevated levels of and effects from the calcium channel blockers, including hypotension,(2,3) shock,(2) and acute kidney failure.(3) In others, elevated levels of the macrolide may occur, which may increase the risk of sudden death from cardiac causes.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid the concurrent use of calcium channel blockers with macrolides that inhibit CYP.(1,2) Depending on the infection, azithromycin may be an alternative in patients maintained on calcium channel blockers.(1) If concurrent use is required, monitor patients for and instruct them to report signs of hypotension, cardiac arrhythmias, or renal failure.

DISCUSSION: A retrospective review examined sudden cardiac death in Tennessee Medicaid patients. Erythromycin use increased the risk of sudden cardiac death by 1.79-fold. Concurrent use of erythromycin with a potent inhibitor of CYP3A4 (diltiazem, fluconazole, itraconazole, ketoconazole, troleandomycin, or verapamil) increased the risk of sudden cardiac death by 5.35-fold when compared to patients receiving no antibiotic therapy.(2) In a retrospective review of residents of Ontario, Canada aged 66 or older who were receiving calcium channel blockers, use of clarithromycin and erythromycin were associated with an increased risk of hospitalization for hypotension (odds ratio 3.7 and 5.8, respectively). There was no association between use of azithromycin and hospitalization for hypotension.(2) In a retrospective review of residents of Ontario, Canada aged 65 or older who were receiving calcium channel blockers, use of clarithromycin was associated with an increased risk of hospitalization with acute kidney injury when compared to use of azithromycin (0.44% of patients versus 0.22% - odds ratio 1.98). Risk was highest with the use of nifedipine (odds ratio 5.33). Use of clarithromycin was also associated with a higher risk of hospitalization with hypotension (0.12% of patients versus 0.07%, odds ratio 1.60) and all-cause mortality (1.02% of patients versus 0.59%, odds ratio 1.74).(3) In a cross-over study in 12 healthy male subjects, the administration of a single dose of felodipine (10 mg extended-release) after four doses of erythromycin (250 mg) resulted in an increase in felodipine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 149%, 127%, and 61%, respectively. Concurrent administration increased dehydrofelodipine AUC, Cmax, and half-life by 92%, 56%, and 93%, respectively, when compared to felodipine administration alone. Concurrent administration of felodipine and erythromycin decreased felodipine M3 metabolite AUC and Cmax concentrations by 41% and 36%, respectively. The extent of the interaction was extremely variable between subjects.(4) In a case report, a 43 year-old female developed palpitations, flushing, ankle edema, and hypotension 2-4 days after the addition of erythromycin to felodipine therapy. Felodipine levels were found to be elevated.(5) In a case report, a 77 year-old male developed shock, heart block, and multi-organ failure two days after the addition of clarithromycin to nifedipine therapy.(6) In a case report, a 76 year-old female developed hypotension, bradycardia, shortness of breath, and weakness two days after the addition of telithromycin to verapamil therapy.(7)

Selected Cyp3a4 Substrates/Ceritinib

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

MECHANISM OF ACTION: Ceritinib inhibits CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of ceritinib with drugs primarily metabolized by CYP3A4 may lead to elevated drug levels and increased side effects of these agents. Drugs with a narrow therapeutic window that are metabolized by this isoenzyme include: cyclosporine, felodipine, hydroquinidine, midazolam, nisoldipine, quinidine, and sirolimus.(1,2)

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP3A4 inhibition. With pimozide, 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: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, dosage adjustment of the CYP3A4 substrate should be considered when initiating or discontinuing ceritinib.(1) Patients maintained on ceritinib may need lower initial doses of the CYP3A4 substrate. Monitor patients receiving concurrent therapy for adverse effects.

DISCUSSION: In a study, ceritinib (750 mg daily for 3 weeks) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (a CYP3A4 substrate) by 5.4-fold and 1.8-fold, respectively, compared to midazolam alone.(1) Thus, ceritinib is expected to increase levels of cyclosporine, felodipine, hydroquinidine, midazolam, nisoldipine, quinidine, and sirolimus.

Selected Cyp3a4 Substrates/Crizotinib

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

MECHANISM OF ACTION: Crizotinib inhibits CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of crizotinib with drugs primarily metabolized by CYP3A4 may lead to elevated drug levels and increased side effects of these agents.(1) Drugs with a narrow therapeutic window that are metabolized by this isoenzyme include: abemaciclib, cisapride, cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam, nisoldipine, quinidine, simvastatin, and sirolimus.(1-2)

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP3A4 inhibition.

PATIENT MANAGEMENT: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, dosage adjustment of the CYP3A4 substrate should be considered when initiating or discontinuing crizotinib.(1) Patients maintained on crizotinib may need lower initial doses of the CYP3A4 substrate. Monitor patients receiving concurrent therapy for adverse effects. Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(3)

DISCUSSION: Crizotinib (250 mg twice daily for 28 days) increased the area-under-curve (AUC) of oral midazolam by 3.7-fold.(1) Thus, crizotinib is expected to increase levels of abemaciclib, cisapride, cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam, nisoldipine, quinidine, and simvastatin.

Selected Cyp3a4 Substrates/Lonafarnib

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

MECHANISM OF ACTION: Lonafarnib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Lonafarnib is also an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of sirolimus.

CLINICAL EFFECTS: Concurrent use of lonafarnib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway or P-gp.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lonafarnib states that coadministration of CYP3A4 substrates should be avoided. If concomitant use is unavoidable, monitor for adverse effects and consider dose reduction of the CYP3A4 substrate according to its prescribing information.(1) The manufacturer of lonafarnib states that the dose of P-gp substrates may need to be reduced with coadministration with lonafarnib.(1)

DISCUSSION: In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam (3 mg) by 639% and 180%, respectively.(1) In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the AUC and Cmax of single-dose fexofenadine (180 mg) by 24% and 21%, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: bromocriptine, cabergoline, cannabidiol-tetrahydrocannabinol, clonazepam, darolutamide, felodipine, mefloquine, nisoldipine, oliceridine, regorafenib, sirolimus, and zanubrutinib.(1-3)

Selected Cyp3a4 Substrates/Pexidartinib

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

MECHANISM OF ACTION: Pexidartinib is a moderate inducer of CYP3A4 and may increase the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of pexidartinib may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pexidartinib states that co-administration of CYP3A4 substrates for which minimal concentration decreases may lead to serious therapeutic failure should be avoided. If concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in accordance with approved product labeling.(1)

DISCUSSION: Coadministration of pexidartinib 400 mg twice daily with oral midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: everolimus, felodipine, fentanyl, hydroquinidine, midazolam, nisoldipine, quinidine, sirolimus, tacrolimus, ticagrelor, and triazolam.(1-3)

Selected Cyp3a4 Substrates/Sotorasib

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

MECHANISM OF ACTION: Sotorasib is a moderate inducer of CYP3A4 and may increase the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of sotorasib may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of sotorasib states that co-administration of CYP3A4 substrates for which minimal concentration decreases may lead to serious therapeutic failure should be avoided. If concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in accordance with approved product labeling.(1)

DISCUSSION: Coadministration of sotorasib with midazolam, a sensitive CYP3A4 substrate, decreased midazolam area-under-curve (AUC) by 53% and maximum concentration (Cmax) by 48%.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: felodipine, fentanyl, hydroquinidine, parenteral lefamulin, midazolam, nisoldipine, quinidine, tacrolimus, ticagrelor, and triazolam.(2,3)

Selected Sensitive Cyp3a4 Substrates/Voxelotor

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

MECHANISM OF ACTION: Voxelotor is an inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of voxelotor may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: A greater risk for serious adverse events would be expected from drugs having a narrow therapeutic window.

PATIENT MANAGEMENT: The manufacturer of voxelotor states that co-administration of sensitive CYP3A4 substrates with a narrow therapeutic index should be avoided. If concomitant use is unavoidable, consider dose reduction of the sensitive substrate.(1)

DISCUSSION: In a study, voxelotor increased the AUC of a single dose of midazolam by 1.6-fold. After multiple doses of midazolam, a 2.5-fold increase in AUC is predicted.(1) Sensitive CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: avanafil, conivaptan, cyclosporine, dihydroergotamine, eplerenone, ergotamine, everolimus, felodipine, fentanyl, lomitapide, lovastatin, methylergonovine, midazolam, nisoldipine, sildenafil, simvastatin, ticagrelor, tolvaptan, triazolam, and vardenafil.(2,3)

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

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)

Felodipine/Selected Cyp3a4 Inhibitors

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 metabolism of felodipine by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of strong CYP3A4 inhibitors may result in elevated levels of felodipine leading to adverse effects, including severe hypotension and peripheral edema.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of felodipine with strong CYP3A4 inhibitors should be approached with caution.(1) When these agents are used concurrently, the dose of felodipine may need to be decreased and patients should be observed for increased effects.(1) If the strong CYP3A4 inhibitor is discontinued, the dose of felodipine may need to be increased and patients should be observed for decreased effects.(1)

DISCUSSION: Concurrent use of an extended release formulation of felodipine with itraconazole resulted in approximately 8-fold increase in the AUC, more than 6-fold increase in the Cmax, and 2-fold prolongation in the half-life of felodipine.(1) A double-blind, randomized, two-phase crossover study in nine subjects examined the effects of itraconazole, a strong CYP3A4 inhibitor, on felodipine. The half-life of felodipine increased by 71% during concurrent itraconazole. In seven of the nine subjects, the maximum concentration (Cmax) of felodipine when administered with placebo was lower than the 32-hour concentration of felodipine when administered with itraconazole. Concurrent use also resulted in significantly greater effects on both blood pressure and heart rate.(1,2) There are two case reports of patients developing edema following the addition of itraconazole to felodipine therapy.(5) In the second report, the patient was rechallenged with concurrent itraconazole and again developed edema.(3) Voriconazole has been shown to inhibit the metabolism of felodipine in vitro.(4) Selected strong CYP3A4 inhibitors linked to this monograph are: adagrasib, cobicistat, conivaptan, ensitrelvir, grapefruit, idelalisib, indinavir, lopinavir, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, relacorilant, ribociclib, ritonavir, saquinavir, troleandomycin, and tucatinib.(5)

Felodipine; Nisoldipine/Selected Azole Antifungals

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

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

CLINICAL EFFECTS: The concurrent administration of azole antifungals with calcium channel blockers metabolized by CYP3A4 may result in elevated levels of the calcium channel blocker and adverse effects, including hypotension and edema.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of azole antifungals 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 decreased and patients should be observed for increased effects. If the azole antifungal is discontinued, the dose of the calcium channel blocker may need to be increased and patients should be observed for decreased effects.

DISCUSSION: A double-blind, randomized, two-phase crossover study in nine subjects examined the effects of itraconazole on felodipine. The half-life of felodipine increased by 71% during concurrent itraconazole. In seven of the nine subjects, the maximum concentration (Cmax) of felodipine when administered with placebo was lower than the 32-hour concentration of felodipine when administered with itraconazole. Concurrent use also resulted in significantly greater effects on both blood pressure and heart rate.(1,2) There are two case reports of patients developing edema following the addition of itraconazole to felodipine therapy. In the second report, the patient was rechallenged with concurrent itraconazole and again developed edema.(3) In a case report, following the withdrawal of fluconazole from concurrent nifedipine therapy, a loss in blood-pressure control occurred.(4) In another report, a patient developed edema following the addition of itraconazole to nifedipine therapy.(5) A randomized cross-over trial in seven subjects examined the effects of ketoconazole (200 mg daily for 4 days) on nisoldipine (5 mg daily). The concurrent use of ketoconazole increased the nisoldipine area-under-curve (AUC) and Cmax by 24-fold and 11-fold, respectively. Increases in the M9 nisoldipine metabolite were similar.(6) Posaconazole has been shown to inhibit CYP3A4.(7,8) Voriconazole has been shown to inhibit the metabolism of felodipine in vitro.(9)

Selected Antihypertensive Agents/Selected Maois

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Selected Antihypertensives And Vasodilators/Apomorphine

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

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

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

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

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

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

Selected Antihypertensives/Tizanidine

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Selected Calcium Channel Blockers/Cimetidine

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

MECHANISM OF ACTION: Cimetidine may decrease the metabolism of diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and nitrendipine.

CLINICAL EFFECTS: The pharmacological effects of the calcium channel blocker may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Observe the patient for changes in clinical response to the calcium channel blocker when starting or stopping cimetidine. The dosage of the calcium channel blocker may need to be adjusted. Ideally, suggest an alternative H-2 antagonist such as famotidine, nizatidine, or ranitidine.

DISCUSSION: Significant effects have been observed during concurrent administration of nifedipine or felodipine with cimetidine. During combined administration of nifedipine and cimetidine in six healthy volunteers, the area-under-curve (AUC) of nifedipine was increased by 80% compared to nifedipine alone. Increased heart rate and a drop in mean arterial pressure 14 mmHg were also reported. Ranitidine showed only a nonsignificant 25% rise in peak plasma levels of nifedipine and no effects on blood pressure. Similar results were reported in another study where concurrent administration of felodipine and cimetidine resulted in an increase in felodipine AUC and maximum concentration (Cmax) by 50%. Concurrent administration of cimetidine has also been shown to increase the AUC and Cmax of diltiazem by 53% and 58%, respectively. The manufacturers of isradipine and nicardipine recommend carefully monitoring patients receiving concurrent therapy with cimetidine. The manufacturer of isradipine states that concurrent therapy with cimetidine has been shown to increase the AUC of isradipine by 50%. The manufacturer of nifedipine states that careful titration is necessary in patients receiving concurrent therapy. The manufacturers of felodipine and diltiazem state that dosage adjustments may be necessary in patients receiving concurrent therapy. Ranitidine has much less affinity for CYP metabolism than cimetidine and would therefore be expected to have less of an effect on calcium channel blocker metabolism. Studies have shown that nizatidine and famotidine do not inhibit CYP3A4 metabolism.

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)

Selected Sensitive Cyp3a4 Substrates/Schisandra

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

MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)

CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)

PREDISPOSING FACTORS: With darifenacin, 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.(8)

PATIENT MANAGEMENT: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) 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.(8)

DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)

Selected Weak Cyp2d6 Inhibitors/Tamoxifen

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

MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence.

PREDISPOSING FACTORS: Concurrent use of weak CYP2D6 inhibitors in patients who are CYP2D6 intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.

PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The National Comprehensive Cancer Network's breast cancer guidelines advises caution when coadministering strong CYP2D6 inhibitors with tamoxifen.(14) NCCN states when prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid SSRIs that are strong and moderate CYP2D6 inhibitors, particularly fluoxetine and paroxetine, if an appropriate alternative exists.(14) Cancer Care Ontario breast cancer guidelines state concurrent use of weak CYP2D6 inhibitors should be closely monitored.(15) The European Society of Medical Oncology (ESMO) clinical practice guidelines for early breast cancer states patients on tamoxifen should be advised to avoid concurrent use of strong and moderate CYP2D6 inhibitors. Consider alternatives to tamoxifen if CYP2D6 inhibitors cannot be replaced with alternative agents.(16) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient.

DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(18) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(19-20) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(21-23) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(24-28) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, chloroquine, cimetidine, clobazam, clomipramine, cobicistat, delavirdine, diltiazem, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, fedratinib, felodipine, fluvoxamine, gefitinib, hydralazine, imatinib, labetalol, lorcaserin, nicardipine, osilodrostat, ranitidine, ritonavir, sarpogrelate, sertraline, verapamil and viloxazine.(29)

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)

Weak Cyp2d6 Inhibitors/Eliglustat

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

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

CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP2D6 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 CYP3A4 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 dosage of eliglustat with weak inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with weak inhibitors of CYP2D6 in extensive CYP2D6 metabolizers 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.

DISCUSSION: Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 7-fold and 8.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-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 terbinafine, a moderate inhibitor of CYP2D6, would increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in extensive metabolizers and by 1.6-fold and 1.6-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) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(5) Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, chloroquine, chlorpromazine, clobazam, clomipramine, desvenlafaxine, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, felodipine, gefitinib, hydralazine, hydroxychloroquine, lorcaserin, methadone, panobinostat, propafenone, sarpogrelate, sertraline, vemurafenib, and venlafaxine.(3,4)

*Known hypersensitivity to felodipine or any ingredient in the formulation.

• Severe hypotension

• Chronic idiopathic constipation
• Hypotension
• Myasthenia gravis
• Severe coronary artery disease

• Chronic heart failure
• Disease of liver
• Peripheral edema

The most common adverse reactions to oral felodipine are peripheral edema, headache, and flushing.

More Frequent

• Peripheral edema

Less Frequent

• Allergic dermatitis
• Angina
• Tachycardia

Rare or Very Rare

• Depression
• Dyspnea
• Gingival hyperplasia
• Severe hypotension
• Skin rash

More Frequent

• Headache disorder

Less Frequent

• Constipation
• Diarrhea
• Dizziness
• Fatigue
• Flushing
• Nausea
• Paresthesia
• Upper respiratory infection

Rare or Very Rare

• Acute abdominal pain
• Arthralgia
• Cough
• Cramps
• Dysuria
• Erectile dysfunction
• Flu-like symptoms
• Gynecomastia
• Increased urinary frequency
• Insomnia
• Pain
• Pharyngitis
• Rhinorrhea
• Syncope
• Visual changes
• Xerostomia

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Although safety and efficacy are not established in children younger than 18 years of age, some experts have recommended oral pediatric dosages+ for hypertension based on clinical experience.

Animal studies indicate felodipine crosses the placenta.

Digital anomalies consisting of reduction in size and degree of ossification of the terminal phalanges have been observed in pregnant rabbits administered oral felodipine dosages from 0.46 to 4.6 mg/kg daily (from 0.8 to 8-times the maximum recommended human dose (MRHD) on a mg/m2 basis and patient body weight of 50 kg); the frequency and severity of such changes appear to be dose-related and noted even at the lowest dose. Similar anomalies were not observed in rats, however an abnormal position of the distal phalanges, but not a reduction in size, was noted in 40% of the fetuses when cynomolgus monkeys received felodipine during a teratology study.

Rats administered felodipine >=9.6 mg/kg daily (8-times MRHD on a mg/m2 basis and patient body weight of 50 kg) experienced prolonged parturition with difficult labor and increased frequency of fetal and postnatal death.

Rabbits administered felodipine >=1.2 mg/kg daily (2.1-times MRHD on a mg/m2 basis and patient body weight of 50 kg) experienced significant mammary gland enlargement in excess of the normal expected enlargement; this effect regressed during lactation and was not observed in rats or monkeys.

There are no adequate and well-controlled studies using felodipine in pregnant women. Women taking felodipine during pregnancy, or who become pregnant while taking felodipine, should be advised of the potential hazards to the fetus (e.g., digital anomalies of the infant), effects on labor and delivery, and on the woman's mammary glands.

It is not known whether felodipine is distributed into human milk. Because of the potential for serious adverse reactions in the infant, a decision should be made to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Dosage of felodipine should be adjusted carefully and blood pressure response should be closely monitored with each adjustment in geriatric patients; the usual initial dosage is 2.5 mg daily. In clinical trials, the risk of peripheral edema was increased substantially in geriatric patients receiving dosages exceeding 10 mg daily.

Clinical studies did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults. Compared to younger individuals, felodipine clearance is decreased and AUC increased in geriatric subjects; felodipine plasma concentrations increase with age following a single dose or at steady-state.

While other clinical experience generally has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range (2.5 mg daily) and adjusting as necessary based on patient response. 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.