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NiCARdipine

Pronunciation

Pronunciation

(nye KAR de peen)

Index Terms

  • Cardene
  • Nicardipine HCl
  • Nicardipine Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as hydrochloride:

Generic: 20 mg, 30 mg

Capsule Extended Release 12 Hour, Oral, as hydrochloride:

Cardene SR: 30 mg [DSC] [contains fd&c red #40]

Cardene SR: 60 mg [DSC] [contains fd&c blue #2 (indigotine)]

Solution, Intravenous, as hydrochloride:

Cardene IV: 20 mg (200 mL); 40 mg (200 mL); 2.5 mg/mL (10 mL [DSC])

Generic: 2.5 mg/mL (10 mL)

Brand Names: U.S.

  • Cardene IV
  • Cardene SR [DSC]

Pharmacologic Category

  • Antianginal Agent
  • Antihypertensive
  • Calcium Channel Blocker
  • Calcium Channel Blocker, Dihydropyridine

Pharmacology

Inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina

Absorption

Oral: ~100%, but large first-pass effect

Distribution

Vd: 8.3 L/kg

Metabolism

Hepatic; extensive first-pass effect (saturable); major pathway is via cytochrome P450 isoenzyme CYP3A4

Excretion

Urine (oral: 60% as metabolites; IV: 49% as metabolites; <1% as unchanged drug); feces (oral: 35%; IV: 43%)

Clearance: Decreased in patients with hepatic dysfunction; may be decreased in patients with renal impairment

Onset of Action

IV: Within minutes (constant infusion); Oral: 0.5 to 2 hours

Peak effect: Immediate capsules: 1-2 hours; Sustained release capsules (at steady state): Sustained from 2-6 hours postdose; IV continuous infusion: 50% of the maximum effect is seen by 45 minutes

Time to Peak

Serum: Oral: Immediate release: 30 to 120 minutes (mean: 1 hour) ; Sustained release: 60 to 240 minutes

Duration of Action

IV: ≤8 hours; Oral: Immediate release: ≤8 hours, Sustained release: 8 to 12 hours; Continuous infusion: Upon discontinuation, a 50% decrease in effect is seen in ~30 minutes with gradual discontinuing antihypertensive effects for ~50 hours.

Half-Life Elimination

Follows dose-dependent (nonlinear) pharmacokinetics; “apparent” or calculated half-life is dependent upon serum concentrations. Half-life over the first 8 hours after oral dosing is 2-4 hours; terminal half-life (oral): 8.6 hours. After IV infusion, serum concentrations decrease tri-exponentially; alpha half-life: 2.7 minutes; beta half-life: 44.8 minutes; terminal half-life: 14.4 hours (Note: Terminal half-life can only be seen after long-term infusions)

Protein Binding

>95%

Special Populations: Renal Function Impairment

IV: Significantly lower systemic clearance and higher area under the curve (AUC) in patients with moderate renal impairment.

Oral: Immediate release: Maximum plasma concentration (Cmax) and AUC were approximately 2-fold higher in patients with mild renal impairment.

Oral: Sustained release: Cmax and AUC were 2-fold to 3-fold higher in patients with moderate renal impairment.

Special Populations: Hepatic Function Impairment

In patients with severe hepatic impairment, plasma concentrations were elevated and the half-life was prolonged

Use: Labeled Indications

Angina: Management of chronic stable angina (oral immediate-release product only)

Hypertension: Management of hypertension (oral immediate- and sustained-release products and IV); parenteral only for short-term use when oral treatment is not feasible or not desirable

The 2014 guideline for the management of high blood pressure in adults (JNC 8) recommends initiation of pharmacologic treatment to lower blood pressure for the following patients (JNC 8 [James 2013]):

• Patients ≥60 years of age with systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg. Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg.

• Patients <60 years of age with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with diabetes with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with chronic kidney disease (CKD) with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

In patients with chronic kidney disease (CKD), regardless of race or diabetes status, the use of an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) as initial therapy is recommended to improve kidney outcomes. In the general nonblack population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic, calcium channel blocker, ACEI, or ARB. In the general black population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic or a calcium channel blocker instead of an ACEI or ARB.

Use: Unlabeled

Control of blood pressure in acute ischemic stroke and spontaneous intracranial hemorrhage, perioperative hypertension, prevention of migraine headaches, subarachnoid hemorrhage associated cerebral vasospasm

Contraindications

Hypersensitivity to nicardipine or any component of the formulation; advanced aortic stenosis

Dosing: Adult

Note: Cardene SR has been discontinued in the US for more than 1 year.

Angina: Immediate release: Oral: 20 mg 3 times daily; usual dosage: 20 to 40 mg 3 times daily (allow ≥3 days between dose increases)

Hypertension: Oral:

Immediate release: Initial: 20 mg 3 times daily; usual dosage: 20 to 40 mg 3 times daily (allow ≥3 days between dose increases)

Sustained release: Initial: 30 mg twice daily; usual dosage: 30 to 60 mg twice daily

Acute hypertension: IV: Initial: 5 mg/hour; may increase by 2.5 mg/hour every 5 minutes (for rapid titration) to every 15 minutes (for gradual titration) up to a maximum of 15 mg/hour; rapidly titrated patients, consider reduction to 3 mg/hour after response is achieved. Discontinue infusion if unacceptable hypotension or tachycardia occurs.

Arterial hypertension in acute ischemic stroke (off-label use [Jauch 2013]): IV:

Patient otherwise eligible for reperfusion treatment (eg, alteplase) except blood pressure (BP) >185/110 mm Hg: Initiate 5 mg/hour; titrate by 2.5 mg/hour at 5- to 15-minute intervals (maximum dose: 15 mg/hour). When goal BP obtained, adjust dose to maintain proper BP limits. If BP does not decline and remains >185/110 mm Hg, alteplase should not be administered.

Management of BP during and after reperfusion treatment (eg, alteplase) to maintain BP ≤180/105 mm Hg: If systolic BP >180 to 230 mm Hg or diastolic >105 to 120 mm Hg: Initiate 5 mg/hour; titrate by 2.5 mg/hour at 5- to 15-minute intervals (maximum dose: 15 mg/hour). If hypertension is refractory or diastolic BP >140 mm Hg, consider other IV antihypertensives (eg, nitroprusside).

Substitution for oral therapy (approximate equivalents):

20 mg every 8 hours oral, equivalent to 0.5 mg/hour IV infusion

30 mg every 8 hours oral, equivalent to 1.2 mg/hour IV infusion

40 mg every 8 hours oral, equivalent to 2.2 mg/hour IV infusion

Conversion to oral antihypertensive agent: Initiate oral antihypertensive at the same time that IV nicardipine is discontinued, if transitioning to oral nicardipine, start oral nicardipine 1 hour prior to IV discontinuation.

Dosing: Geriatric

Initiate at the low end of the dosage range. Specific guidelines for adjustment of nicardipine are not available, but careful monitoring is warranted and adjustment may be necessary.

Dosing: Renal Impairment

Oral: Per the manufacturer: Initial: 20 mg 3 times daily (immediate release) or 30 mg twice daily (sustained release) with slow titration.

IV: There are no dosage adjustments provided in the manufacturer’s labeling; titrate slowly with careful monitoring; dosage adjustment may be necessary.

Dosing: Hepatic Impairment

Oral: Per the manufacturer: Initial: 20 mg twice daily (immediate release) with slow titration.

IV: There are no dosage adjustments provided in the manufacturer’s labeling; titrate slowly with monitoring; dosage adjustment may be necessary.

Reconstitution

IV: Vial: Dilute 25 mg vial with 240 mL of compatible solution to provide a 250 mL total volume solution and a final concentration of 0.1 mg/mL.

Premixed bags: No further dilution needed.

Administration

Oral: The total daily dose of immediate-release product may not automatically be equivalent to the daily sustained-release dose; use caution in converting. Administer without regards to meals; nicardipine sustained release administered with a meal may reduce the fluctuation in plasma levels. Do not chew or crush the sustained release formulation, swallow whole. Do not open or cut capsules.

IV:

Administer as a slow continuous infusion via central line or through a large peripheral vein. Peripheral venous irritation may be minimized by changing the site of infusion every 12 hours.

Premixed bags: Do not combine or run in the same line as other medications.

Dietary Considerations

Avoid grapefruit juice.

Compatibility

Stable in D5W with KCl 40 mEq, D51/2NS, D5NS, D5W, NS, 1/2NS; incompatible with sodium bicarbonate 5%.

Y-site administration: Incompatible with ampicillin, ampicillin/sulbactam, cefepime, furosemide, micafungin, thiopental.

Storage

IV:

Premixed bags: Store at 20°C to 25°C (68°F to 77°F). Protect from light and excessive heat. Do not freeze.

Vials: Store at 20°C to 25°C (68°F to 77°F). Protect from light. Freezing does not adversely affect the product, but exposure to elevated temperatures should be avoided. Diluted solution (0.1 mg/mL) in D5W with KCl 40 mEq, D51/2NS, D5NS, D5W, NS, or 1/2NS is stable at room temperature for 24 hours in glass or PVC containers. Stability has also been demonstrated at room temperature at concentrations up to 0.5 mg/mL in PVC containers for 24 hours or in glass containers for up to 7 days (Baaske 1996).

Oral: Store at room temperature. Protect from light.

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Alitretinoin (Systemic): CYP2C9 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP2C9 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP2C9 inhibitor. Consider therapy modification

Alpha1-Blockers: May enhance the hypotensive effect of Calcium Channel Blockers. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May enhance the adverse/toxic effect of Calcium Channel Blockers. Specifically, itraconazole may enhance the negative inotropic effects of verapamil or diltiazem. Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Fluconazole and isavuconazonium likely exert weaker effects than other azoles and are addressed in separate monographs. Management: Concurrent use of felodipine or nisoldipine with itraconazole is specifically contraindicated. Frequent monitoring is warranted with any such combination; calcium channel blocker dose reductions may be required. Exceptions: Fluconazole; Isavuconazonium Sulfate. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Atosiban: Calcium Channel Blockers may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Monitor therapy

Barbiturates: May increase the metabolism of Calcium Channel Blockers. Management: Monitor for decreased therapeutic effects of calcium channel blockers with concomitant barbiturate therapy. Calcium channel blocker dose adjustments may be necessary. Nimodipine Canadian labeling contraindicates concomitant use with phenobarbital. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): Calcium Channel Blockers (Dihydropyridine) may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

Calcium Salts: May diminish the therapeutic effect of Calcium Channel Blockers. Monitor therapy

Cannabis: May increase the serum concentration of CYP2C9 Inhibitors (Strong). More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

CarBAMazepine: May increase the metabolism of Calcium Channel Blockers (Dihydropyridine). Management: Consider calcium channel blocker (CCB) dose adjustments or alternative therapy in patients receiving concomitant carbamazepine. Nimodipine Canadian labeling contraindicates concurrent use with carbamazepine. Consider therapy modification

Carvedilol: NiCARdipine may enhance the hypotensive effect of Carvedilol. NiCARdipine may precipitate signs of heart failure in susceptible patients on Carvedilol NiCARdipine may increase the serum concentration of Carvedilol. Monitor therapy

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Citalopram: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a moderate CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CycloSPORINE (Systemic): Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Monitor therapy

CYP2C9 Substrates: CYP2C9 Inhibitors (Strong) may decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the orthostatic hypotensive effect of Calcium Channel Blockers. Monitor therapy

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Diclofenac (Systemic): CYP2C9 Inhibitors (Strong) may increase the serum concentration of Diclofenac (Systemic). Management: Consider using a lower dose of diclofenac when used together with a strong CYP2C9 inhibitor. Arthrotec (diclofenac and misoprostol) labeling specifically recommends limiting the total daily dose to a maximum of 50 mg twice/day. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Efavirenz: May decrease the serum concentration of Calcium Channel Blockers. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fluconazole: May increase the serum concentration of Calcium Channel Blockers. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosphenytoin: Calcium Channel Blockers may increase the serum concentration of Fosphenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of NiCARdipine. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Lacosamide: NiCARdipine may increase the serum concentration of Lacosamide. Management: Lacosamide prescribing information cautions that a lacosamide dose reduction may be warranted in patients with renal dysfunction or mild-moderate hepatic impairment who are also using a strong inhibitor of CYP2C9 and CYP3A4, such as delavirdine. Consider therapy modification

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Calcium Channel Blockers. Management: Consider using a noninteracting macrolide. Felodipine Canadian labeling specifically recommends avoiding its use in combination with clarithromycin. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Magnesium Salts: Calcium Channel Blockers may enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers. Monitor therapy

Melatonin: May diminish the antihypertensive effect of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nafcillin: May increase the metabolism of Calcium Channel Blockers. Consider therapy modification

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Neuromuscular-Blocking Agents (Nondepolarizing): Calcium Channel Blockers may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Ospemifene: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Parecoxib: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Perhexiline: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phenytoin: Calcium Channel Blockers may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Calcium Channel Blockers. Management: Avoid use of nimodipine or nifedipine with phenytoin. Monitor for phenytoin toxicity and/or decreased calcium channel blocker effects with any concurrent use. Consider therapy modification

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Ramelteon: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers. Management: The labeling for some US and Canadian calcium channel blockers contraindicate use with rifampin, however recommendations vary. Consult appropriate labeling. Consider therapy modification

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

SUNItinib: NiCARdipine may increase the serum concentration of SUNItinib. Monitor therapy

Tacrolimus (Systemic): Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Tetrahydrocannabinol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Adverse Reactions

1% to 10%:

Cardiovascular: Flushing (6% to 10%), pedal edema (dose related; 7% to 8%), exacerbation of angina pectoris (dose related; 6%), hypotension (IV 6%), palpitations (3% to 4%), tachycardia (1% to 4%), chest pain (IV 1%), extrasystoles (IV 1%), hemopericardium (IV 1%), hypertension (IV 1%), supraventricular tachycardia (IV 1%), edema (≤1%)

Central nervous system: Headache (6% to 15%), dizziness (4% to 7%), hypoesthesia (1%), intracranial hemorrhage (1%), pain (1%), somnolence (1%)

Dermatologic: Diaphoresis (1%), skin rash (≤1%)

Endocrine & metabolic: Hypokalemia (IV 1%)

Gastrointestinal: Nausea and vomiting (IV 5%), nausea (2%), dyspepsia (≤2%), abdominal pain (IV 1%), xerostomia (≤1%)

Genitourinary: Hematuria (1%)

Local: Injection site reaction (IV 1%), pain at injection site (IV 1%)

Neuromuscular & skeletal: Weakness (4% to 6%), myalgia (1%), paresthesia (1%)

<1% (Limited to important or life-threatening): Abnormal dreams, abnormal hepatic function tests, abnormal vision, angina pectoris, arthralgia, atrial fibrillation (not distinguishable from natural history of atherosclerotic vascular disease), cerebral ischemia (not distinguishable from natural history of atherosclerotic vascular disease), conjunctivitis, deep vein thrombophlebitis, depression, ECG abnormal, gingival hyperplasia, heart block (not distinguishable from natural history of atherosclerotic vascular disease), hot flash, hyperkinesia, hypersensitivity reaction, hypertonia, hypophosphatemia, hypotension (exertional; not distinguishable from natural history of atherosclerotic vascular disease), myocardial infarction (chronic therapy; may be due to disease progression), neck pain, nervousness, oxygen saturation decreased (possible pulmonary shunting), parotitis, pericarditis (not distinguishable from natural history of atherosclerotic vascular disease), peripheral vascular disease, respiratory tract disease, sinus node dysfunction (chronic therapy; may be due to disease progression), sustained tachycardia, thrombocytopenia, tinnitus, tremor, urinary frequency, ventricular extrasystoles, ventricular tachycardia, vertigo

Warnings/Precautions

Concerns related to adverse effects:

• Angina/MI: Increased angina (frequency, duration, or severity) and/or MI has occurred with initiation or dosage titration of dihydropyridine calcium channel blockers. Reflex tachycardia may occur resulting in angina and/or MI in patients with obstructive coronary disease, especially in the absence of concurrent beta blockade.

• Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Avoid systemic hypotension in acute cerebral infarction or hemorrhage. Close monitoring of blood pressure, especially during initial therapy and dosage titration, is required.

• Peripheral edema: A common side effect is peripheral edema (dose-dependent); occurs within 2 to 3 weeks of starting therapy.

• Tachycardia: May occur; close monitoring of heart rate is required.

Disease-related concerns:

• Aortic stenosis: Use with caution in patients with mild to moderate aortic stenosis; may reduce coronary perfusion resulting in ischemia. Use is contraindicated in patients with advanced aortic stenosis.

• Heart failure (HF): Use in patients with severe left ventricular dysfunction, particularly with concomitant beta-blockade, may experience worsened symptoms of HF due to mild negative inotropic effects of nicardipine. The ACCF/AHA heart failure guidelines recommend to avoid use in patients with heart failure due to lack of benefit and/or worse outcomes with calcium channel blockers in general (Yancy 2013).

• Hepatic impairment: Use with caution in patients with hepatic impairment or reduced hepatic blood flow. Consider lower starting dose and closely monitor response.

• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Use with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition.

• Renal impairment: Use with caution in patients with renal impairment. Increase dose cautiously in patients with renal impairment since clearance of nicardipine is diminished in this population.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Initiate at the low end of the dosage range.

Dosage form specific issues:

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007).

Other warnings/precautions:

• Infusion sites: To minimize infusion site reactions, peripheral infusion sites (for IV therapy) should be changed every 12 hours; use of small peripheral veins should be avoided.

• Withdrawal: Abrupt withdrawal may cause rebound angina in patients with CAD.

Monitoring Parameters

Blood pressure, heart rate; consult individual institutional policies and procedures

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Nicardipine has been used for the treatment of severe hypertension in pregnancy and preterm labor. Nicardipine crosses the placenta; changes in fetal heart rate, neonatal hypotension and neonatal acidosis have been observed following maternal use (rare; based on limited data). Adverse effects reported in pregnant women are generally similar to those reported in nonpregnant patients; however, pulmonary edema has been observed (Nij 2010). Untreated chronic maternal hypertension is also associated with adverse events in the fetus, infant, and mother. If treatment for hypertension during pregnancy is needed, other agents are preferred (ACOG 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?

• Patient may experience flushing, headache, loss of strength and energy, vomiting, or nausea. Have patient report immediately to prescriber severe dizziness, passing out, arrhythmia, angina, tachycardia, shortness of breath, excessive weight gain, swelling of arms or legs, or injection site irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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