Cardene I.V. (nicardipine HCl)

Nicardipine is commercially available as nicardipine hydrochloride; dosage is expressed in terms of the salt.

Nicardipine hydrochloride is usually administered orally, but may be administered by IV infusion for the short-term treatment of hypertension when oral administration is not feasible or desired. For prolonged control of blood pressure, patients should be transferred to oral therapy as soon as their clinical condition permits. Some experts state that nicardipine hydrochloride may be administered as an IV bolus+ or infusion in children and adolescents with acute severe hypertension and life-threatening symptoms.

No dosing information is available for this tab.

No dosing information is available for this tab.

Nicardipine is a substrate of cytochrome P-450 (CYP) isoenzyme 3A4, 2C8, and 2D6. Nicardipine inhibits CYP3A4, 2D6, 2C8, and 2C19. Nicardipine does not induce or inhibit its own metabolism.

There are no contraindication interactions for this drug.

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)

Nicardipine/Tacrolimus

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

MECHANISM OF ACTION: Nicardipine may inhibit the metabolism of tacrolimus by CYP3A4.(1-7)

CLINICAL EFFECTS: Concurrent use of nicardipine may result in elevated levels of and side effects from tacrolimus, including nephrotoxicity, prolongation of the QTc interval and life-threatening cardiac arrhythmias, torsades de pointes, graft dysfunction, and increased risk of infections.(1-7)

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 nicardipine is initiated or discontinued. The dosage of tacrolimus may need to be adjusted or nicardipine may need to be discontinued. Consider an alternative antihypertensive agent, such as labetalol. When concurrent therapy of nicardipine 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: In a clinical study, eight patients who were CYP3A5 non-expressors had a higher median concentration maximum (Cmax) than both four patients CYP3A5 expressors and controls (24.3 ng/ml, 13.9 ng/mL, and 14.6 ng/ml, respectively). Compared to the other two groups, CYP3A5 non-expressors had higher dose adjusted Cmax, less time to Cmax, and more scheduled tacrolimus doses held per patient. Six of eight CYP3A5 non-expressors had potentially toxic Cmax levels (> 20 ng/ml) compared with none of four CYP3A5 expressors and 11.25% of control group.(5) A case report of a 20-year-old kidney transplant patient on tacrolimus 5 mg twice daily, mycophenolate mofetil, and prednisone was started on intravenous nicardipine. Twelve hours after starting nicardipine, the tacrolimus trough level was 16.3 ng/mL (target range 12-18 ng/mL). Tacrolimus dose was reduced.(6)

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)

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

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 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/Digoxin

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 renal clearance of digoxin through an unknown mechanism.

CLINICAL EFFECTS: Plasma digoxin concentrations may be elevated. In addition, the negative chronotropic effects of digoxin and bepridil are additive, resulting in a cumulative decrease in heart rate. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

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

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor serum digoxin levels and observe the patient for symptoms of digoxin toxicity. Upon adding a calcium channel blocker, digoxin should first be decreased in anticipation of interaction, then adjust the dosage accordingly. The dosage of digoxin may need to be decreased by 15-50% or the frequency of administration may be reduced.

DISCUSSION: The effect of bepridil on steady-state serum digoxin levels was studied in a randomized, double-blind investigation. Concurrent administration of bepridil and digoxin produced a 34% increase in serum digoxin levels compared to administration of digoxin alone. Concomitant administration of both drugs was associated with additive negative chronotropic effects. Information on the effects of diltiazem on digoxin concentrations are conflicting. Several studies have reported that concurrent use of digoxin and diltiazem led to an increased steady state digoxin level as well as an increased digoxin area-under-curve (AUC) and decreased renal clearance, and reduced volume of distribution. However, one of these studies reported no significant change in digoxin half-life, peak concentration (Cmax), time to Cmax (Tmax), or volume of distribution, and seven other studies reported no effect of diltiazem on serum digoxin concentrations or renal digoxin clearance. Concomitant isradipine administration significantly decreased (by 9%) the the digoxin volume of distribution and increased (by 25%) digoxin Cmax; however, the digoxin steady state serum concentration, AUC, and renal clearance were not affected. In patients with congestive heart failure on digoxin therapy, the addition of felodipine resulted in a significant increase in digoxin Cmax attained following oral administration. This increase was most notable in patients with high felodipine serum concentrations. Digoxin trough levels and six hour post-dose levels were unaffected; as were digoxin AUC measurements. There is one case report of an interaction between nifedipine and digoxin; however, a study in 28 patients found no effect of nifedipine on digoxin. A study in ten subjects showed that nisoldipine increased digoxin levels by 15%. Information on the effects of nicardipine on digoxin kinetics is conflicting. One study in twenty patients showed no effect of nicardipine on digoxin. One study in ten subjects showed a significant increase in digoxin levels: however, this was seen in only one subject. Concurrent nitrendipine has been shown to increase digoxin serum levels by 57% and digoxin AUC by 15%. Concurrent diltiazem has been shown to increase digoxin serum concentration by 20%. Concurrent nifedipine has been shown to increase digoxin serum concentration by 45%.

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/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: 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.(10,11) 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.(7) PKPB modeling of nifedipine and ritonavir noted a decreased systolic blood pressure > 40 mmHg.(8) There are several case reports of patients developing increased levels of calcium channel blockers and adverse effects with concurrent strong CYP3A4 inhibitors.(9-16) Strong CYP3A4 inhibitors include: adagrasib, ceritinib, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, relacorilant, ribociclib, saquinavir, tipranavir, troleandomycin, tucatinib, and voriconazole.(17,18)

Selected Calcium Channel Blockers/Temsirolimus

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 sirolimus by CYP3A4.(1) Sirolimus is the active metabolite of temsirolimus.(2) Therefore, temsirolimus is expected to be affected in the same manner as sirolimus.

CLINICAL EFFECTS: Concurrent use of calcium channel blockers may result in elevated levels of and side effects from temsirolimus.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of temsirolimus states that if an agent inhibiting CYP3A4 is prescribed and alternative treatment cannot be used, a dose adjustment of temsirolimus should be considered.(2)

DISCUSSION: The pharmacokinetics of temsirolimus was not affected by ketoconazole, a strong CYP3A4 inhibitor. However, sirolimus area-under-curve (AUC) increased 3.1-fold and maximum concentration (Cmax) increased 2.2-fold compared to temsirolimus alone.(2) 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.(1,3) Nicardipine may increase sirolimus levels.(1) 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.(1) In a study in 25 healthy subjects, concurrent sirolimus with verapamil increased sirolimus Cmax and AUC 130% and 120%, respectively.(4)

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)

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)

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

*Advanced aortic stenosis, since reduction in diastolic pressure may worsen myocardial oxygen balance.

• Severe aortic valve stenosis

• Chronic heart failure
• Disease of liver
• Intracerebral hemorrhage

• Angina
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Kidney disease with likely reduction in glomerular filtration rate (GFr)

The most common adverse reactions to oral nicardipine are pedal edema (7.1%, dose-related), dizziness (6.9%), headache (6.4%), asthenia (5.8%), flushing (5.6%), increased angina (5.6%, dose-related), palpitations (3.3%), and nausea (1.9%).

The most common adverse reactions to IV nicardipine are headache (13 -15%), hypotension (5 -6%), tachycardia (4%), and nausea/vomiting (4 -5%).

More Frequent

• Tachycardia

Rare or Very Rare

• Abnormal ECG
• Acute myocardial infarction
• Angina
• Atrioventricular block
• Deep venous thrombosis
• Hypophosphatemia
• Hypoxia
• Peripheral edema
• Severe hypotension
• Sinus node dysfunction
• Thrombocytopenic disorder

More Frequent

• Headache disorder
• Hypotension
• Nausea
• Vomiting

Rare or Very Rare

• Acute cognitive impairment
• Conjunctivitis
• Dyspepsia
• Fever
• Hypertonia
• Increased urinary frequency
• Injection site sequelae
• Neck pain
• Thrombophlebitis
• Tinnitus

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Although safety and efficacy of oral or IV nicardipine remain to be established in pediatric patients younger than 18 years of age, some experts have recommended IV pediatric dosages+ for severe hypertension based on clinical experience.

Nicardipine hydrochloride has been shown to be embryocidal in pregnant rabbits when given at an oral daily dose of 150 mg/kg during organogenesis but not at a daily dose of 50 mg/kg (8 times the maximum recommended human dosage). There was no evidence of embryotoxicity or teratogenicity when nicardipine hydrochloride was administered IV at dosages up to 5 mg/kg daily in pregnant rats or up to 0.5 mg/kg daily in pregnant rabbits. Embryolethality was observed at IV dosages of 10 mg/kg daily (equivalent to a human IV dosage of 1.6 mg/kg daily) in rats and 1 mg/kg daily (equivalent to a human IV dosage of 0.32 mg/kg daily) in rabbits, but there was no evidence of teratogenicity at these dosages. No adverse effects on the fetus were observed when New Zealand albino rabbits received nicardipine hydrochloride dosages up to 100 mg/kg daily during organogenesis. Pregnant rats receiving oral nicardipine hydrochloride at dosages up to 100 mg/kg daily (50 times the maximum recommended human dosage) did not exhibit evidence of embryolethality or teratogenicity but did exhibit evidence of dystocia, reduced birthweights, reduced neonatal survival, and reduced neonatal weight gain.

There are no adequate and well-controlled studies using nicardipine in pregnant women. Hypotension, reflex tachycardia, postpartum hemorrhage, tocolysis, headache, nausea, dizziness, and flushing have been reported in pregnant women who were treated with IV nicardipine for hypertension during pregnancy. Fetal effects ranged from transient fetal heart rate decelerations to no adverse events; neonatal effects ranged from hypotension to no adverse events. Adverse events in women treated with IV nicardipine during pre-term labor include pulmonary edema, dyspnea, hypoxia, hypotension, tachycardia, headache, and phlebitis at the site of injection; neonatal adverse events include acidosis (pH<7.25).

Nicardipine crosses the placenta, but fetal plasma concentrations are only approximately 10% of concurrent maternal plasma concentrations.

Nicardipine should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Nicardipine is distributed into milk in high concentrations in rats and minimally excreted into human milk. In a small number of women receiving nicardipine postpartum, infants received an average of 0.073 and 0.14% of the weight-adjusted maternal dose following oral and IV nicardipine administration, respectively. In another small study of women receiving immediate postpartum IV nicardipine for the treatment of preeclampsia, the maximum dose in the breastfed neonate was estimated to be <0.3 mcg daily or 0.004-0.015% of the therapeutic dose in a 1 kg neonate.

Some manufacturers recommend against breastfeeding while receiving nicardipine, while others recommend to consider the possibility of infant exposure from breastfeeding.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

When nicardipine hydrochloride was administered at doses of 10, 20, and 30 mg three times daily, plasma drug concentrations in elderly hypertensive subjects were similar to plasma concentrations in healthy young adult subjects suggesting that the pharmacokinetics of nicardipine hydrochloride are similar in young and elderly hypertensive patients. Clinical studies of nicardipine did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger patients. While other clinical experience generally has not revealed age-related differences in pharmacokinetics, response, or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. The frequencies of pedal edema may be higher in geriatric patients than in younger adults, while the frequencies of flushing and headache may be lower. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly should be considered.