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    Dihydropyridine Calcium Channel Blockers

    DEA CLASS

    Rx

    DESCRIPTION

    Oral and IV dihydropyridine calcium-channel blocker; primarily used for chronic angina, HTN, hypertensive emergency or urgency; mechanism similar to nifedipine, except it is more selective for cerebral and coronary blood vessels; also lacks intrinsic decrease in myocardial contractility.

    COMMON BRAND NAMES

    Cardene, Cardene IV, Cardene SR

    HOW SUPPLIED

    Cardene IV/Nicardipine/Nicardipine Hydrochloride Intravenous Inj Sol: 0.1mg, 0.2mg, 1mL, 2.5mg
    Cardene SR Oral Cap ER: 30mg, 45mg
    Cardene/Nicardipine/Nicardipine Hydrochloride Oral Cap: 20mg, 30mg

    DOSAGE & INDICATIONS

    For the treatment of chronic stable angina.
    Oral dosage (regular-release capsules)
    Adults

    Initially, 20 mg PO 3 times daily. Titrate to response. The usual dosage is 20—40 mg PO 3 times daily.

    For the treatment of hypertension.
    For chronic hypertension.
    Oral dosage (regular-release capsules)
    Adults

    Initially, 20 mg PO 3 times daily. Titrate to response. The usual dosage is 20—40 mg PO 3 times daily.

    Oral dosage (sustained-release capsules)
    Adults

    Initially, 30 mg PO twice daily. Increase to 60 mg PO twice daily if necessary.

    For short-term treatment of hypertension when oral therapy is not feasible or desirable; or for the treatment of hypertensive urgency† or hypertensive emergency†, except in the setting of acute heart failure.
    Intravenous dosage
    Adults

    Initiate therapy at 5 mg/hour as a continuous IV infusion. For gradual reduction in blood pressure (BP), increase infusion rate, if needed, by 2.5 mg/hour every 15 minutes to a temporary maximum of 15 mg/hour. For rapid BP reduction, the initial infusion rate of 5 mg/hour IV may be increased, if needed, by 2.5 mg/hour every 5 minutes to a maximum of 15 mg/hour. Once BP goal has been achieved, decrease infusion rate to 3 mg/hour IV. Switch to oral therapy as soon as possible.

    Neonates†, Infants†, Children†, and Adolescents†

    A suggested initial starting dosage is 0.5—1 mcg/kg/minute by continuous IV infusion. Titrate to attain blood pressure goals up to a maximum of 4—5 mcg/kg/minute by IV infusion. The usual dosage range is approximately 1—3 mcg/kg/minute continuous IV infusion. Infusion rates of 0.5—2 mcg/kg/minute have been used safely to treat hypertensive neonates. One institution has reported experience with a higher initial dosage of 5 mcg/kg/minute IV infusion to rapidly attain blood pressure goals (5—15 minutes), with a subsequent decrease to a maintenance IV infusion rate (1—3 mcg/kg/minute). To limit infusing large IV volumes in pediatric patients, nicardipine has been infused at concentrations as high as 50 mg per 100 mL (0.5 mg/mL). This concentration has been administered via peripheral catheter; however, administration using a central catheter is suggested when possible to reduce the risk of phlebitis. Continuous blood pressure monitoring is recommended during IV nicardipine infusion; reflex tachycardia may occur.

    For postoperative hypertension†, in the absence of supraventricular tachycardia or a recent myocardial infarction.
    Intravenous dosage
    Adults

    In one clinical trial, 139 patients with postoperative hypertension were randomized to receive either nicardipine or nitroprusside. The initial dose of nicardipine was 10 mg/hour as an IV infusion for 5 minutes, which was titrated, if needed, to 12.5 mg/hour for 5 minutes, then up to 15 mg/hour for a maximum of 15 minutes until therapeutic response was achieved. If a therapeutic response was achieved, the nicardipine dose was decreased to 3 mg/hour IV for 15 minutes and subsequently adjusted by 1—2.5 mg/hour to maintain BP control. Therapeutic response (i.e., greater than 15% BP reduction from pretreatment baseline) was achieved in 86% of the nicardipine-treated group versus 88% of the nitroprusside-treated group.

    For the treatment of proteinuria† associated with diabetic nephropathy†.
    Oral dosage (regular-release capsules)
    Adults

    An initial dose of 20 mg PO 3 times daily, titrated to achieve clinical goals, has been used. Nicardipine effectively and significantly reduces blood pressure and urinary albumin excretion.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    120 mg/day PO regular-release capsules or sustained-release capsules; or 15 mg/hr IV infusion for up to 15 minutes until therapeutic response is achieved.

    Elderly

    120 mg/day PO regular-release capsules or sustained-release capsules; or 15 mg/hr IV infusion for up to 15 minutes until therapeutic response is achieved.

    Adolescents

    Safety and efficacy have not been established; however, up to 5 mcg/kg/min IV infusion has been administered for severe hypertension.

    Children

    Safety and efficacy have not been established; however, up to 5 mcg/kg/min IV infusion has been administered for severe hypertension.

    Infants

    Safety and efficacy have not been established; however, up to 5 mcg/kg/min IV infusion has been administered for severe hypertension.

    Neonates

    Safety and efficacy have not been established; however, up to 5 mcg/kg/min IV infusion has been administered for severe hypertension.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The manufacturer advises caution in patients with hepatic impairment or reduced hepatic blood flow; reduced dosage is suggested for the regular-release formulation. Initially, 20 mg PO twice daily for regular-release capsules; titrate the dosage to response using a twice daily interval.

    Renal Impairment

    No initial dosage adjustment is needed; however, careful dose titration is advised when treating renally impaired patients. Begin with the initial adult dosage, and cautiously adjust the nicardipine dosage based on clinical response.
     
    Intermittent hemodialysis
    Nicardipine is not significantly removed by hemodialysis.

    ADMINISTRATION

    Oral Administration

    Although food decreases both peak concentrations and extent of absorption of nicardipine, efficacy trials were performed without regard to meals. Therefore, meal-induced variability was taken into account.
    Avoid taking nicardipine with grapefruit juice or grapefruit (see Drug Interactions).

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Dosage conversion/substitution from oral to IV nicardipine therapy for adults:
    -If patient is receiving 20 mg PO every 8 hours, initiate infusion at IV at 0.5 mg/hour.
    -If patient is receiving 30 mg PO every 8 hours, initiate infusion at IV at 1.2 mg/hour.
    -If patient is receiving 40 mg PO every 8 hours, initiate infusion at IV at 2.2 mg/hour.
     
    Concentrated ampules:
    Nicardipine injection is compatible with the following IV solutions: dextrose (5%) water, dextrose (5%) water and sodium chloride (0.45%), dextrose (5%) water and sodium chloride (0.9%), dextrose (5%) water with 40 mEq potassium chloride, sodium chloride (0.45%), and sodium chloride (0.9%). Nicardipine injection is not compatible with sodium bicarbonate (5%), or lactated ringer's.
    Dilute ampules prior to infusion. Dilute each ampul (25 mg/10 ml) with 240 ml of a compatible IV fluid to make 250 ml of IV solution. The final concentration recommended by the manufacturer is 0.1 mg/ml. NOTE: To limit infusing large IV fluid volumes in hypertensive pediatric patients†, nicardipine has been infused at concentrations as high as 50 mg per 100 ml (0.5 mg/ml). This concentration has been administered via peripheral catheter; however, administration using a central catheter is suggested when possible to reduce the risk of phlebitis at the injection site.
     
    Prefilled flexible infusion containers:
    Supplied as single-use, ready-to-use intravenous bags available as 20 mg nicardipine hydrochloride in 200 mL of either dextrose or sodium chloride (0.1 mg/mL) or 40 mg nicardipine hydrochloride in 200 mL of either dextrose or sodium chloride (0.2 mg/mL).
     
    Intravenous infusion:
    Administer by slow IV infusion. To reduce the risk of extravasation, phlebitis, and venous thrombosis, administer nicardipine through large peripheral veins or central veins. Do not administer through arteries or small peripheral veins, such as those on the dorsum of the hand or wrist. If administering through a peripheral vein, the infusion site should be changed every 12 hours to minimize the risk of peripheral venous irritation.
    Monitor blood pressure and heart rate during and after the infusion; avoid too rapid or excessive blood pressure drop during treatment. When used for the treatment of hypertensive emergency, intra-arterial blood pressure monitoring may be necessary, especially for patients with labile and difficult to control blood pressure.

    STORAGE

    Cardene:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Cardene IV:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Cardene SR:
    - Store at room temperature (between 59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Dihydropyridine hypersensitivity

    Nicardipine is a dihydropyridine calcium-channel blocker and is contraindicated in patients with known serious dihydropyridine hypersensitivity.

    Acute myocardial infarction, bradycardia, cardiogenic shock, heart failure, ventricular dysfunction

    Nicardipine should be used cautiously in patients with severe bradycardia, acute myocardial infarction with concomitant pulmonary congestion, or congestive heart failure (or left ventricular dysfunction) because nicardipine can precipitate or exacerbate heart failure due to its negative inotropic effects, particularly in patients receiving concomitant beta-blocker therapy. The development or worsening of pulmonary edema is a marker for discontinuation of nicardipine. Nicardipine is relatively contraindicated in cardiogenic shock.

    Hypotension

    Nicardipine decreases peripheral resistance and can worsen hypotension. Nicardipine should not be used in patients with systolic blood pressures of less than 90 mm Hg (i.e., severe hypotension). Nicardipine should be used with caution in patients with mild to moderate hypotension. Blood pressure should be monitored carefully in all patients receiving nicardipine.

    Aortic stenosis

    Nicardipine is contraindicated in patients with advanced aortic stenosis because the abnormal pressure gradient associated with this condition can worsen with nicardipine therapy.

    Intracranial bleeding, stroke

    Nicardipine should be used with great caution in patients with an acute stroke or intracranial bleeding because the sequelae of these conditions can be worsened if the patient develops systemic hypotension.

    Geriatric, renal failure, renal impairment

    Geriatric patients and patients with renal impairment or renal failure, can experience a delayed clearance of nicardipine and can be at greater risk for accumulation and toxicity. Uremia may inhibit the metabolism of nicardipine. Titrate dosage gradually when treating renally impaired patients.

    Hepatic disease

    Since nicardipine is metabolized in the liver, the drug should be used with caution in patients with impaired liver function, hepatic disease (e.g., cirrhosis) or reduced hepatic blood flow. The use of lower dosages should be considered in patients with hepatic impairment. Nicardipine administered intravenously has been reported to increase the hepatic venous pressure gradient by 4 mmHg in cirrhotic patients at high doses (5 mg/20 min). Therefore, intravenous nicardipine should be used with caution in patients with portal hypertension.

    Neonates, pregnancy

    Nicardipine is classified as FDA pregnancy risk category C. There are no adequate and well-controlled studies of nicardipine use in pregnant women. However, limited human data in pregnant women with preeclampsia or pre-term labor are available. According to the manufacturer, nicardipine should be used during pregnancy only when its benefits to the mother clearly outweigh the risks to the fetus. Hypotension, reflex tachycardia, postpartum hemorrhage, tocolysis, headache, nausea, dizziness, and flushing have been reported in pregnant women who were treated with intravenous nicardipine for hypertension during pregnancy. Fetal safety results ranged from transient fetal heart rate decelerations to no adverse events. Safety data in exposed neonates ranged from hypotension to no adverse events. Adverse events in women treated with intravenous nicardipine during pre-term labor include pulmonary edema, dyspnea, hypoxia, hypotension, tachycardia, headache, and phlebitis at site of injection. Neonatal adverse events included acidosis (pH < 7.25).

    Breast-feeding

    According to the manufacturer, nicardipine is minimally excreted into human milk. Among 18 infants exposed to nicardipine through breast milk in the post-partum period, the calculated daily infant dose was less than 0.3 mcg or between 0.015 to 0.004% of the therapeutic dose in a 1 kg infant; no adverse events were observed. The American Academy of Pediatrics (AAP) has not evaluated the use of nicardipine in breast-feeding mothers; however, the AAP regards nifedipine, a related medication, as usually compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    Safety and efficacy in neonates, infants, children and adolescents less than 18 years old have not been established by the manufacturer. However, intravenous (IV) nicardipine has been administered to hypertensive pediatric patients including neonates, infants, children, and adolescents. To limit infusing large IV fluid volumes in pediatric patients, nicardipine has been infused at concentrations as high as 50 mg per 100 ml (0.5 mg/ml). The higher IV solution concentration has been administered via peripheral catheter; however, administration using a central catheter is suggested when possible to reduce the risk of injection site phlebitis. Continuous blood pressure monitoring is recommended during nicardipine IV infusion. Reflex tachycardia may occur.

    Gastroesophageal reflux disease (GERD), hiatal hernia

    Calcium channel blockers, like nicardipine, should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. The drugs relax the lower esophageal sphincter.

    Pheochromocytoma

    Use intravenous nicardipine with caution in patients with hypertension from pheochromocytoma, as limited clinical experience exists.

    Angina

    Induction and exacerbation of angina has been reported in coronary artery disease and angina pectoris patients treated with nicardipine. Nicardipine may increase the frequency, duration, or severity of angina with initiation of therapy or dose titration. Though the mechanism of this effect is not fully established, angina may result from excessive hypotension, coronary steal, or reflex tachycardia. Patients with angina should be observed for worsening symptoms when nicardipine is begun, particularly if beta-blocker therapy is being withdrawn.

    Extravasation

    Nicardipine should be administered through a central or large peripheral vein to reduce the possibility of extravasation, venous thrombosis, phlebitis, local irritation, swelling, and rarely vascular impairment. Avoid arteries and small peripheral veins, such as those on the dorsum of the hand or wrist. Peripheral infusion sites should be changed every 12 hours to minimize the risk of venous irritation.

    ADVERSE REACTIONS

    Severe

    atrial fibrillation / Early / 0-1.0
    myocardial infarction / Delayed / 0-1.0
    pericarditis / Delayed / 0-1.0
    ventricular tachycardia / Early / 0-1.0
    AV block / Early / 0-1.0
    thrombosis / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    visual impairment / Early / Incidence not known

    Moderate

    peripheral edema / Delayed / 5.9-8.0
    hypotension / Rapid / 0.9-8.0
    angina / Early / 1.0-7.0
    sinus tachycardia / Rapid / 0.8-5.0
    palpitations / Early / 2.8-4.1
    chest pain (unspecified) / Early / 0-1.0
    edema / Delayed / 1.0-1.0
    orthostatic hypotension / Delayed / 1.0-1.0
    confusion / Early / 0-1.0
    depression / Delayed / 0-1.0
    constipation / Delayed / 0.6-0.6
    ST-T wave changes / Rapid / Incidence not known
    peripheral vasodilation / Rapid / Incidence not known
    wheezing / Rapid / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    hypophosphatemia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    hot flashes / Early / Incidence not known
    hypertonia / Delayed / Incidence not known
    gingival hyperplasia / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known

    Mild

    headache / Early / 6.2-21.0
    flushing / Rapid / 9.7-9.7
    vomiting / Early / 0.4-7.0
    nausea / Early / 1.9-7.0
    dizziness / Early / 1.6-6.9
    asthenia / Delayed / 0.9-5.2
    dyspepsia / Early / 0.8-1.5
    xerostomia / Early / 0.4-1.4
    drowsiness / Early / 1.1-1.4
    anxiety / Delayed / 0-1.0
    paresthesias / Delayed / 1.0-1.0
    syncope / Early / 0.8-0.8
    malaise / Early / 0.6-0.6
    insomnia / Early / 0.6-0.6
    tremor / Early / 0.6-0.6
    fatigue / Early / Incidence not known
    infection / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    nocturia / Early / Incidence not known
    vertigo / Early / Incidence not known
    hyperkinesis / Delayed / Incidence not known
    increased urinary frequency / Early / Incidence not known
    sinusitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    fever / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    diaphoresis / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: Although concomitant therapy with nicardipine and acebutolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), acebutolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Acetaminophen; Butalbital: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Acetaminophen; Butalbital; Caffeine: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Acetaminophen; Butalbital; Caffeine; Codeine: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Dextromethorphan; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Acetaminophen; Dichloralphenazone; Isometheptene: Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended.
    Acetaminophen; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Hydrocodone: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone.
    Acetaminophen; Oxycodone: Coadministration of nicardipine, a CYP3A4 inhibitor according to in vitro data, and oxycodone, a CYP3A4 substrate, may increase oxycodone plasma concentrations and increase or prolong related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patient for an extended period of time and adjust dosage as necessary; oxycodone dosage adjustments may be needed if the CYP3A4 inhibitor is discontinued. Concurrent administration of oxycodone and voriconazole, another CYP3A4 inhibitor, increased oxycodone AUC by 3.6-fold and the Cmax by 1.7-fold.
    Acetaminophen; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Acrivastine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Afatinib: If the concomitant use of nicardipine and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of nicardipine. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and nicardipine is a strong P-gp inhibitor in vitro; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Aldesleukin, IL-2: Calcium channel blockers may potentiate the hypotension seen with aldesleukin, IL 2.
    Alemtuzumab: Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Alfentanil: Alfentanil may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with alfentanil is increased in patients receiving calcium-channel blockers. In addition to additive hypotensive effects, calcium-channel blockers that are CYP3A4 inhibitors (e.g., diltiazem, nicardipine, and verapamil) can theoretically decrease hepatic metabolism of some opiates (CYP3A4 substrates), such as alfentanil. Diltiazem increases the half-life of alfentanil by 50% via inhibition of cytochrome P450 (CYP) 3A4 metabolism and may delay tracheal extubation after anesthesia. Reduced clearance of alfentanil should be considered when recovery from alfentanil infusions for anesthesia is evaluated in patients receiving concurrent diltiazem therapy.
    Alfuzosin: The concomitant administration of alpha-blockers with other antihypertensive agents can cause additive hypotensive effects. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Alosetron: Alosetron is partially metabolized by CYP3A4. Nicardipine may inhibit this enzyme and decrease the metabolism of alosetron resulting in increased alosetron plasma concentrations. Coadministration of alosetron with nicardipine has not been studied.
    Alprazolam: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including alprazolam.
    Alprostadil: The concomitant use of systemic alprostadil injection and antihypertensive agents, like calcium channel blockers, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Ambrisentan: Ambrisentan is a substrate for P-glycoprotein transport, an energy-dependent drug efflux pump, OATP, and CYP3A4. The inhibition of P-glycoprotein, by drugs such as nicardipine, may lead to a decrease in the intestinal metabolism and an increase in the oral absorption of ambrisentan. Coadministration of cyclosporine, a strong inhibitor of P-glycoprotein, OATP, and CYP3A4, with ambrisentan resulted in an approximate 2-fold and 1.5-fold increase in the AUC and Cmax of ambrisentan, respectively. If ambrisentan is coadministered with a P-glycoprotein inhibitor, patients should be monitored closely for adverse effects.
    Amide local anesthetics: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Amifostine: Patients receiving antihypertensive agents should be closely monitored during amifostine infusions due to additive effects. If possible, patients should not take their antihypertensive medication 24 hours before receiving amifostine. Patients who can not stop their antihypertensive agents should not receive amifostine or be closely monitored during the infusion and, possibly, given lower doses.
    Amiodarone: Caution should be used when CYP3A4 inhibitors, such as amiodarone, are co-administered with nicardipine, which is a CYP3A4 substrate and inhibitor.
    Amitriptyline; Chlordiazepoxide: CYP3A4 inhibitors, such as nicardipine, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
    Amlodipine; Atorvastatin: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including atorvastatin.
    Amobarbital: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Amoxicillin; Clarithromycin; Lansoprazole: Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. A retrospective, case cross-over study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent.
    Amoxicillin; Clarithromycin; Omeprazole: Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. A retrospective, case cross-over study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent.
    Amphetamine; Dextroamphetamine Salts: Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as calcium-channel blockers. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Amprenavir: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Amyl Nitrite: Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Apomorphine: Patients receiving apomorphine may experience orthostatic hypotension, hypotension, and/or syncope. Extreme caution should be exercised if apomorphine is used concurrently with antihypertensive agents, or vasodilators such as nitrates.
    Apraclonidine: Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.
    Aprepitant, Fosaprepitant: Avoid the concomitant use of nicardipine with aprepitant due to substantially increased exposure of aprepitant. If coadministration cannot be avoided, use caution and monitor for an increase in aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Nicardipine is a moderate CYP3A4 inhibitor in vitro, and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur.
    Aripiprazole: Because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as nicardipine. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena extended-release intramuscular dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving 662 mg or 882 mg of Aristada extended-release injection every 4 weeks should have their Aristada dose reduced to the next lower strength if a potent CYP2D6 inhibitor, such as nicardipine, is used for more than 14 days. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. For patients receiving Aristada 882 mg every 6 weeks, reduce the dose to 441 mg every 4 weeks. Avoid use of combination therapy with a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days in patients receiving 662 mg or 882 mg of Aristada; no dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated.
    Artemether; Lumefantrine: Nicardipine is a substrate/inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. Nicardipine is a substrate/inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Articaine; Epinephrine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Asenapine: Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Aspirin, ASA; Butalbital; Caffeine: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Aspirin, ASA; Oxycodone: Coadministration of nicardipine, a CYP3A4 inhibitor according to in vitro data, and oxycodone, a CYP3A4 substrate, may increase oxycodone plasma concentrations and increase or prolong related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patient for an extended period of time and adjust dosage as necessary; oxycodone dosage adjustments may be needed if the CYP3A4 inhibitor is discontinued. Concurrent administration of oxycodone and voriconazole, another CYP3A4 inhibitor, increased oxycodone AUC by 3.6-fold and the Cmax by 1.7-fold.
    Atazanavir: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Atazanavir; Cobicistat: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. Coadministration of cobicistat with nicardipine may result in elevated cobicistat serum concentrations. Cobicistat is a substrate and inhibitor of CYP3A4 and CYP2D6. Nicardipine is a strong inhibitor of CYP2D6 and also inhibits the CYP3A4.
    Atenolol: Although concomitant therapy with nicardipine and atenolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), atenolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Atenolol; Chlorthalidone: Although concomitant therapy with nicardipine and atenolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), atenolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Atomoxetine: Administer atomoxetine and nicardipine with caution. Because atomoxetine is primarily metabolized by CYP2D6, concurrent use of strong CYP2D6 inhibitors such as nicardipine may theoretically increase the risk of atomoxetine-induced adverse effects. In children and adolescents up to 70 kg receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg and adults receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. If concurrent use is necessary, monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation) during concurrent use.
    Atorvastatin: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including atorvastatin.
    Atorvastatin; Ezetimibe: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including atorvastatin.
    Atracurium: Calcium-channel blockers may prolong neuromuscular blockade.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Avanafil: Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including nicardipine, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Axitinib: Use caution if coadministration of axitinib with nicardipine is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Nicardipine is a moderate CYP3A4 and CYP2C19 inhibitor in vitro. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents.
    Azithromycin: Both nicardipine and azithromycin are P-glycoprotein (P-gp) inhibitors and substrates, so coadministration may lead to increased concentrations of either agent. Monitor patients for increased side effects if these drugs are given together.
    Baclofen: Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Barbiturates: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity. Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Bendroflumethiazide; Nadolol: Although concomitant therapy with nicardipine and nadolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), nadolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Benzonatate: Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Benzphetamine: Benzphetamine can increase both systolic and diastolic blood pressure and may counteract the activity of calcium-channel blockers. This represents a pharmacodynamic, and not a pharmacokinetic, interaction. Close monitoring of blood pressure, especially in patients who are taking antihypertensive agents, may be needed
    Betaxolol: Although concomitant therapy with nicardipine and betaxolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), betaxolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Bisoprolol: Although concomitant therapy with nicardipine and bisoprolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), bisoprolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Bisoprolol; Hydrochlorothiazide, HCTZ: Although concomitant therapy with nicardipine and bisoprolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), bisoprolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Black Cohosh, Cimicifuga racemosa: Actein and certain acids isolated from the rhizome of Cimicifuga spp. have been noted to antagonize the influx of calcium and norepinephrine-induced contraction of the aorta in rats. Black cohosh, Cimicifuga racemosa has potentiated the effects of antihypertensive medications in some animal studies, and actein may have peripheral vasodilatory activity. Clinical reports of interactions between black cohosh and antihypertensive agents in humans are not available, and remain theoretical. However, isolated cases of hypertension or hypotension have been reported with black cohosh use.
    Boceprevir: Close clinical monitoring is advised when administering nicardipine with boceprevir due to increased potential for nicardipine-related adverse events. When used in combination, the plasma concentrations of nicardipine were increased. If nicardipine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment.
    Bortezomib: Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
    Bosentan: Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with calcium-channel blockers. In addition, bosentan may induce hepatic metabolism of calcium-channel blockers metabolized by CYP3A4 isoenzymes. Diltiazem and verapamil have potential to inhibit CYP3A4 metabolism of bosentan. Bosentan has been shown to have no pharmacokinetic interactions with nimodipine.
    Brexpiprazole: Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving a strong CYP2D6 inhibitor and one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Nicardipine is a moderate inhibitor of CYP3A4 and a potent inhibitor of CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. It should be noted that no dosage adjustment is needed in patients taking a strong CYP2D6 inhibitor who are receiving brexpiprazole as adjunct treatment for major depressive disorder because CYP2D6 considerations are already factored into general dosing recommendations.
    Brimonidine; Timolol: Although concomitant therapy with nicardipine and timolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), timolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Bromocriptine: Bromocriptine is a cytochrome P450 3A4 substrate. In theory, inhibitors of this isoenzyme, such as nicardipine, may decrease the metabolism of the drug. Additive hypotension may also occur with coadministration.
    Brompheniramine; Carbetapentane; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Brompheniramine; Guaifenesin; Hydrocodone: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Brompheniramine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Budesonide: Nicardipine may increase plasma concentrations of budesonide due to inhibition of the CYP3A4 isoenzyme. Use caution when budesonide is coadministered with drugs that inhibit CYP3A enzymes and consider dose reduction.
    Budesonide; Formoterol: Nicardipine may increase plasma concentrations of budesonide due to inhibition of the CYP3A4 isoenzyme. Use caution when budesonide is coadministered with drugs that inhibit CYP3A enzymes and consider dose reduction.
    Bupivacaine Liposomal: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Bupivacaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Bupivacaine; Lidocaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Buspirone: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including buspirone.
    Butabarbital: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Cabazitaxel: Cabazitaxel is a substrate for P-glycoprotein (Pgp). No formal drug interaction studies have been conducted with Pgp inhibitors, such as nifedipine. Use caution when cabazitaxel is administered concomitantly with Pgp inhibitors.
    Cabergoline: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Coadministration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as cabergoline. Cabergoline has minimal affinity for adrenergic receptors; however, it has been associated with hypotension in some instances. Cabergoline should be used cautiously in those receiving antihypertensive agents.
    Cabozantinib: Monitor for an increase in cabozantinib-related adverse events if concomitant use with nicardipine is necessary. Cabozantinib is primarily metabolized by CYP3A4 and nicardipine is a CYP3A4 inhibitor in vitro. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Caffeine; Ergotamine: Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity.
    Canagliflozin: Canagliflozin is a substrate of drug transporter P glycoprotein (P-gp). Nicardipine is a potent PGP inhibitor in vitro and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control.
    Canagliflozin; Metformin: Canagliflozin is a substrate of drug transporter P glycoprotein (P-gp). Nicardipine is a potent PGP inhibitor in vitro and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control.
    Carbamazepine: Carbamazepine may induce the hepatic metabolism of calcium-channel blockers by the CYP3A4 isoenzyme; which reduces the oral bioavailability of the calcium channel blockers by increasing their presystemic clearance.
    Carbetapentane; Chlorpheniramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Diphenhydramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Phenylephrine; Pyrilamine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Carbidopa; Levodopa: Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Carbinoxamine; Hydrocodone; Phenylephrine: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Carbinoxamine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbinoxamine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Cariprazine: Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Nicardipine is a moderate inhibitor of CYP3A4 and may reduce the hepatic metabolism of CYP3A4 substrates, although the impact of moderate CYP3A4 inhibitors on cariprazine metabolism has not been studied. Monitoring for adverse effects, such as CNS effects and extrapyramidal symptoms, is advisable during coadministration. In addition, orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Carteolol: Although concomitant therapy with nicardipine and carteolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), carteolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Carvedilol: Although concomitant therapy with nicardipine and carvedilol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), carvedilol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Celecoxib: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ceritinib: Ceritinib is a substrate of CYP3A4 and the efflux transporter P-glycoprotein (P-gp); nicardipine is a strong P-glycoprotein inhibitor, and also inhibits CYP3A4. Increased concentrations of ceritinib are possible if it is coadministered with nicardipine; exercise caution.
    Cetirizine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlophedianol; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlordiazepoxide: CYP3A4 inhibitors, such as nicardipine, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
    Chlordiazepoxide; Clidinium: CYP3A4 inhibitors, such as nicardipine, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
    Chloroprocaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlorpheniramine; Hydrocodone: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Chlorpheniramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Cilostazol: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as cilostazol.
    Cimetidine: Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system and has been shown to increase the oral bioavailability of nicardipine. Patients should be monitored closely and lower doses of nicardipine may be considered during concomitant therapy with cimetidine.
    Cisapride: Post-marketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Nicardipine may have the potential to inhibit the metabolism of cisapride through CYP3A4 and thus, should not be used with cisapride.
    Cisatracurium: Calcium-channel blockers may prolong neuromuscular blockade.
    Citalopram: The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with nicardipine, a CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg per day in patients receiving CYP2C19 inhibitors.
    Clarithromycin: Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. A retrospective, case cross-over study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent.
    Clobazam: A dosage reduction of clobazam may be necessary during co-administration of nicardipine. Metabolism of the active metabolite of clobazam occurs primarily through CYP2C19 and nicardipine is an inhibitor of CYP2C19 in vitro. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
    Clonazepam: CYP3A4 inhibitors, such as nicardipine, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
    Clopidogrel: Administer clopidogrel and nicardipine together with caution. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps. The CYP3A4 isoenzyme is involved in one of the metabolic steps, and the CYP2C19 isoenzyme is involved in both steps. Nicardipine is an inhibitor of CYP2C19 and CYP3A4. When clopidogrel and omeprazole, a potent CYP2C19 inhibitor, are coadministered, the plasma concentrations of the active metabolite of clopidogrel and platelet inhibition activity are reduced. Monitor for reduced efficacy of clopidogrel if coadministered with nicardipine.
    Clorazepate: Nicardipine is a CYP3A4 inhibitor and may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity.
    Clozapine: Caution is advisable during concurrent use of nicardipine and clozapine. Nicardipine is an inhibitor of CYP3A4 and CYP2D6, two of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP2D6 or CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary.
    Cobicistat: Coadministration of cobicistat with nicardipine may result in elevated cobicistat serum concentrations. Cobicistat is a substrate and inhibitor of CYP3A4 and CYP2D6. Nicardipine is a strong inhibitor of CYP2D6 and also inhibits the CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Coadministration of cobicistat with nicardipine may result in elevated cobicistat serum concentrations. Cobicistat is a substrate and inhibitor of CYP3A4 and CYP2D6. Nicardipine is a strong inhibitor of CYP2D6 and also inhibits the CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Caution is advised when administering tenofovir, a P-gp substrate, concurrently with inhibitors of P-gp, such as nicardipine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. Coadministration of cobicistat with nicardipine may result in elevated cobicistat serum concentrations. Cobicistat is a substrate and inhibitor of CYP3A4 and CYP2D6. Nicardipine is a strong inhibitor of CYP2D6 and also inhibits the CYP3A4.
    Cobimetinib: Avoid the concurrent use of cobimetinib with chronic nicardipine therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of nicardipine is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of nicardipine, resume cobimetinib at the previous dose. Use an alternative to nicardipine in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; in vitro, nicardipine is a moderate inhibitor of CYP3A as well as a strong P-gp inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
    Cod Liver Oil: Fish oil supplements may cause mild, dose-dependent reductions in systolic or diastolic blood pressure in untreated hypertensive patients. Relatively high doses of fish oil are required to produce any blood pressure lowering effect. Additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Codeine; Phenylephrine; Promethazine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Co-Enzyme Q10, Ubiquinone: Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Colchicine: As colchicine is a substrate of CYP3A4 and P-glycoprotein and nicardipine is a substrate and inhibitor of CYP3A4 and P-glycoprotein, increased concentrations of colchicine are expected with concurrent use. Dosage adjustments of colchicine are recommended if given concurrently with such medications. Colchicine accumulation may be greater in patients with renal or hepatic impairment.
    Conivaptan: Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor, and nicardipine, a CYP3A4/P-gp substrate. Coadministration may result in elevated concentrations of nicardipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as nicardipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    Crizotinib: Concomitant use of crizotinib and nicardipine may result in increased concentrations of both agents. Crizotinib is a CYP3A4 and P-glycoprotein (PGP) substrate/inhibitor, while nicardipine is a CYP3A4 substrate/inhibitor and PGP substrate/inhibitor. Monitor patients for toxicity with coadministration.
    Cyclobenzaprine: The CYP3A4 enzyme and CYP1A2 enzyme are primarily responsible for the hepatic metabolism of cyclobenzaprine. Theoretically, levels of cyclobenzaprine could rise due to inhibition at the 3A4 enzyme. Observe the patient for enhanced side effects, such as CNS depression, if cyclobenzaprine and CYP3A4 inhibitors, including nicardipine, are co-administered.
    Cyclophosphamide: Use caution if cyclophosphamide is used concomitantly with nicardipine, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Nicardipine is a moderate in vitro CYP2C19 and 3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Cyclosporine: Coadministration of nicardipine and cyclosporine may result in elevated plasma cyclosporine concentrations. Monitor plasma concentrations of cyclosporine closely, and adjust the dose as necessary. Cyclosporine is extensively metabolized by CYP3A4 and is a substrate of the P-glycloprotein (P-gp) drug transporter; nicardipine is an inhibitor of both CYP3A4 and P-gp.
    Dabigatran: Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with nicardipine, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like nicardipine in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with nicardipine, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Daclatasvir: Concurrent administration of daclatasvir, a CYP3A4 substrate, with nicardipine, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Dalfopristin; Quinupristin: Dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme, including nicardipine.
    Danazol: Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Dantrolene: Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Darunavir: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Darunavir; Cobicistat: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. Coadministration of cobicistat with nicardipine may result in elevated cobicistat serum concentrations. Cobicistat is a substrate and inhibitor of CYP3A4 and CYP2D6. Nicardipine is a strong inhibitor of CYP2D6 and also inhibits the CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Elevated plasma concentrations and an increased risk of serious adverse events may occur with coadministration of nicardipine and dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir and nicardipine both prolong the PR interval and the manufacturer for ritonavir recommends caution during coadministration. The metabolic interactions that may occur are complex, with increased plasma concentrations and, thus, adverse reactions of all 5 drugs anticipated. Nicardipine is a CYP2C8 inhibitor, a CYP2D6 potent inhibitor, a CYP3A4 substrate/ inhibitor, and a P-glycoprotein (P-gp) transport substrate/potent inhibitor. Ritonavir is a CYP2D6 substrate/inhibitor, a CYP3A4 substrate/potent inhibitor, and a P-gp substrate/inhibitor. Paritaprevir is a substrate of CYP3A4 and P-gp. Dasabuvir is a substrate of CYP2C8, CYP3A4, and P-gp. Ombitasvir is a P-gp substrate. Caution and close monitoring are advised if these drugs are administered together. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Dasatinib: Dasatinib inhibits CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme, such as calcium-channel blockers, are administered concurrently with dasatinib as increased adverse reactions may occur. Diltiazem, nicardipine and verapamil may also inhibit the metabolism of dasatinib.
    Delavirdine: Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as nicardipine, should be expected with concurrent use of delavirdine.
    Desloratadine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Dexmedetomidine: In general, the concomitant administration of dexmedetomidine with antihypertensive agents could lead to additive hypotensive effects. Dexmedetomidine can produce bradycardia or AV block and should be used cautiously in patients who are receiving antihypertensive drugs that lower the heart rate such as calcium-channel blockers.
    Dexmethylphenidate: Dexmethylphenidate may reduce the hypotensive effect of antihypertensive agents, such as calcium-channel blockers. Methylphenidate reduces the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial co-administration and after dosage increases of methylphenidate.
    Dextromethorphan; Diphenhydramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Dextromethorphan; Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Dextromethorphan; Quinidine: Quinidine concentrations decrease by 20 to 40% when nicardipine is added and rise after nicardipine is withdrawn. Although this appears to be an idiosyncratic reaction, quinidine doses may need to be adjusted when nicardipine is added or withdrawn. Careful monitoring of serum quinidine concentrations is prudent following the addition or discontinuation of nicardipine.
    Diazepam: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including diazepam.
    Diazoxide: Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents.
    Diclofenac: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diclofenac; Misoprostol: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diethylpropion: Diethylpropion has vasopressor effects and may limit the benefit of calcium-channel blockers. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
    Diflunisal: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Digoxin: Some calcium-channel blockers cause serum digoxin concentrations to rise. Although this reaction has not been reported with nicardipine, patients should be monitored closely for this possibility if nicardipine is added to digoxin therapy.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Dihydroergotamine: Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Diphenhydramine; Hydrocodone; Phenylephrine: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Diphenhydramine; Ibuprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diphenhydramine; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Disopyramide: Because nicardipine inhibits CYP3A4, the metabolism of disopyramide may be inhibited.
    Dofetilide: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including doeftilide.
    Dorzolamide; Timolol: Although concomitant therapy with nicardipine and timolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), timolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Doxacurium: Calcium-channel blockers may prolong neuromuscular blockade.
    Doxorubicin: In vitro, nicardipine is a potent CYP2D6 and P-glycoprotein (P-gp) inhibitor as well as a moderate CYP3A4 inhibitor; doxorubicin is a major substrate of CYP2D6, CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of nicardipine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronabinol, THC: Use caution if coadministration of dronabinol with nicardipine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; nicardipine is a moderate inhibitor of CYP3A4 in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Diltiazem and verapamil are inhibitors of CYP3A4 and substrates of CYP3A and P-gp; nifedipine and amlodipine are substrates for CYP3A4. In clinical trials, the coadministration of dronedarone and calcium-channel blockers (diltiazem, verapamil, and nifedipine) resulted in an increase in exposure of calcium channel blockers by 1.4 to 1.5 fold and an increase in dronedarone exposure by 1.4 to1.7 fold. Furthermore, calcium channel blockers may potentiate the electrophysiologic effects of dronedarone (e.g., decreased AV and sinus node conduction). If coadministration of calcium channel blockers and dronedarone cannot be avoided, administer low doses of the calcium channel blocker and increase dosage only after ECG verification of tolerability.
    Drospirenone; Ethinyl Estradiol: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Drospirenone; Ethinyl Estradiol; Levomefolate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Duloxetine: Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
    Dutasteride; Tamsulosin: The concomitant administration of tamsulosin with other antihypertensive agents can cause additive hypotensive effects. In addition, diltiazem, nicardipine, and verapamil may increase tamsulosin plasma concentrations via CYP3A4 inhibition. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Edoxaban: Coadministration of edoxaban and nicardipine may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and nicardipine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of nicardipine; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: Use caution and careful monitoring when coadministering efavirenz with certain calcium-channel blockers. Efavirenz induces CYP3A4, potentially altering serum concentrations of calcium-channel blockers metabolized via CYP3A4. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments are made based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, lercanidipine, nicardipine, and verapamil); adjust based on clinical response.
    Efavirenz; Emtricitabine; Tenofovir: Caution is advised when administering tenofovir, a P-gp substrate, concurrently with inhibitors of P-gp, such as nicardipine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. Use caution and careful monitoring when coadministering efavirenz with certain calcium-channel blockers. Efavirenz induces CYP3A4, potentially altering serum concentrations of calcium-channel blockers metabolized via CYP3A4. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments are made based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, lercanidipine, nicardipine, and verapamil); adjust based on clinical response.
    Elbasvir; Grazoprevir: Administering elbasvir; grazoprevir with nicardipine may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nicardipine is a moderate inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity. Administering elbasvir; grazoprevir with nicardipine may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nicardipine is a moderate inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eletriptan: Eletriptan may reduce the effectiveness of antihypertensive agents. Patients on antihypertensives need to have their blood pressure adequately controlled if they are to receive eletriptan. If eletriptan is used, regular blood pressure monitoring is recommended.
    Eliglustat: Coadministration of nicardipine and eliglustat should be avoided. Eliglustat is a CYP3A and CYP2D6 substrate; in vitro studies have indicated nicardipine is a relatively potent inhibitor of CYP2D6 and CYP3A4. In general, use of eliglustat with both a strong or moderate CYP2D6 inhibitor and a strong or moderate CYP3A inhibitor is contraindicated in all patients. Coadministration may increase eliglustat exposure through both metabolic pathways and significantly increase the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Empagliflozin: Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Empagliflozin; Linagliptin: Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Empagliflozin; Metformin: Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: Close clinical monitoring is advised when administering nicardipine with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nicardipine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: Caution is advised when administering tenofovir, a P-gp substrate, concurrently with inhibitors of P-gp, such as nicardipine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. Close clinical monitoring is advised when administering nicardipine with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nicardipine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Emtricitabine; Tenofovir disoproxil fumarate: Caution is advised when administering tenofovir, a P-gp substrate, concurrently with inhibitors of P-gp, such as nicardipine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Enflurane: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Ephedrine: The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by calcium-channel blockers. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Epirubicin: Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant treatment with epirubicin and calcium-channel blockers. Individuals receiving these medications concurrently are at increased risk of developing heart failure.
    Eplerenone: Eplerenone is metabolized by the CYP3A4 pathway. Nicardipine inhibits the hepatic CYP3A4 isoenzyme and therefore may increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. If these medications are given concurrently in post-myocardial infarction patients with heart failure, do not exceed an eplerenone dose of 25 mg PO once daily. If these medications are given concurrently, and eplerenone is used for hypertension, initiate eplerenone at 25 mg PO once daily. The dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response.
    Epoprostenol: Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Ergoloid Mesylates: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Coadministration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as ergoloid mesylates.
    Ergonovine: Because of its potential to cause coronary vasospasm, ergonovine could theoretically antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. In addition, calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergonovine and increase the risk of ergot toxicity.
    Ergotamine: Because of the potential to cause coronary vasospasm , ergotamine theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergotamine and increase the risk of ergot toxicity.
    Erlotinib: Use caution if coadministration of erlotinib with nicardipine is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both nicardipine and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Nicardipine is a moderate CYP3A4 inhibitor in vitro. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with nicardipine may also increase erlotinib exposure.
    Erythromycin: Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapami) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Erythromycin; Sulfisoxazole: Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapami) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Escitalopram: The plasma concentration of escitalopram, a CYP2C19 and CYP3A4 substrate, may be increased when administered concurrently with nicardipine, a CYP2C19 and CYP3A4 inhibitor. If these drugs are used together, monitor for escitalopram-associated adverse reactions.
    Esmolol: Although concomitant therapy with nicardipine and esmolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), esmolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Esomeprazole; Naproxen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Estazolam: Nicardipine is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
    Estradiol Cypionate; Medroxyprogesterone: Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Estradiol: Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Ethanol: Ethanol interacts with antihypertensive agents by potentiating their hypotensive effect.
    Ethinyl Estradiol: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Desogestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Ethynodiol Diacetate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Etonogestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norelgestromin: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone Acetate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norgestimate: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norgestrel: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethosuximide: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as ethosuximide.
    Ethotoin: Hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers and thereby reduce their oral bioavailability. The dosage requirements of nicardipine may be increased in patients receiving concurrent hydantoin anticonvulsants.
    Etodolac: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Etomidate: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Etoposide, VP-16: Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with nicardipine. In vitro, nicardipine is a strong inhibitor of P-glycoprotein (P-gp) as well as a CYP3A4 inhibitor; etoposide, VP-16 is a CYP3A4 and P-gp substrate. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations.
    Everolimus: Everolimus is an inhibitor and substrate of CYP3A4 and Pgp. Coadministration with strong or moderate inhibitors of CYP3A4 or Pgp, such as nicardipine, is not recommended. Patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered. In addition, nicardipine is a substrate of CYP3A4. The effect of everolimus on nicardipine pharmacokinetics has not been established; however, pharmacokinetic studies showed no significant impact of the coadministration of everolimus with the CYP3A4 and Pgp substrate atorvastatin.
    Ezetimibe; Simvastatin: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including simvastatin.
    Famotidine; Ibuprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Fenoprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Fentanyl: Concomitant use of calcium channel blockers and fentanyl, especially in combination with beta-adrenergic blocking agents during surgical procedures, has resulted in severe hypotension. As is recommended with other calcium channel blockers, nicardipine should be withheld for at least 36 hours, if possible, prior to the use of high-dose fentanyl. In addition to the potential for hypotensive effects, nicardipine, a CYP3A4 inhibitor, can theoretically inhibit hepatic metabolism of some opiate agonists, CYP3A4 substrates, such as fentanyl.
    Fexofenadine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10. High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Flibanserin: The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as nicardipine, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
    Fluconazole: Fluconazole may decrease the clearance of calcium-channel blockers, including nicardipine, via inhibition of CYP3A4 metabolism.
    Fluoxetine: Fluoxetine may decrease the clearance of calcium-channel blockers, including nicardipine, via inhibition of CYP3A4 metabolism.
    Fluoxetine; Olanzapine: Fluoxetine may decrease the clearance of calcium-channel blockers, including nicardipine, via inhibition of CYP3A4 metabolism. Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Flurazepam: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including flurazepam.
    Flurbiprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Fluvoxamine: Caution should be used when CYP3A4 inhibitors, such as fluvoxamine, are co-administered with nicardipine, a CYP3A4 substrate and inhibitor.
    Food: The incidence of marijuana associated adverse effects may change following coadministration with nicardipine. Nicardipine is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with nicardipine, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosamprenavir: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Fosphenytoin: Hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers and thereby reduce their oral bioavailability. The dosage requirements of nicardipine may be increased in patients receiving concurrent hydantoin anticonvulsants.
    Fospropofol: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Galantamine: Hepatic CYP3A4 is partially responsible for the metabolism of galantamine. The bioavailability of galantamine may be theoretically increased when co-administered with the CYP3A4 inhibitor nicardipine; this interaction has not been studied.
    Gefitinib: Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and nicardipine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, nicardipine is a moderate CYP3A4 inhibitor and a strong inhibitor of CYP2D6. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. In patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated.
    General anesthetics: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Ginkgo, Ginkgo biloba: Ginkgo biloba appears to inhibit the metabolism of calcium-channel blockers, perhaps by inhibiting the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that the concurrent administration of ginkgo with nifedipine resulted in a 53% increase in nifedipine peak concentrations. More study is needed regarding ginkgo's effects on CYP3A4 and whether clinically significant drug interactions result.
    Ginseng, Panax ginseng: Ginseng appears to inhibit the metabolism of calcium-channel blockers, perhaps by inhibiting the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that the concurrent administration of ginseng with nifedipine resulted in a 30% increase in nifedipine peak concentrations. More study is needed regarding ginseng's effects on CYP3A4 and whether clinically significant drug interactions result.
    Grapefruit juice: Grapefruit juice contains compounds that inhibit the cytochrome P-450 CYP3A4 isozyme in the gut wall. Grapefruit juice can increase the serum concentrations and oral bioavailability of nicardipine. Co-administration of oral nicardipine with grapefruit juice significantly increases the AUC and peak plasma concentrations of nicardipine; the half-life of nicardipine is not affected. Grapefruit juice does not affect the pharmacokinetics of IV nicardipine. It is generally recommended to avoid grapefruit juice ingestion during nicardipine therapy.
    Guaifenesin; Hydrocodone: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Guaifenesin; Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Guaifenesin; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Halofantrine: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including halofantrine.
    Haloperidol: In general, antipsychotics like haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension. In addition, nicardipine is an inhibitor of CYP2D6 and CYP3A4, the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and substrates or inhibitors of CYP3A4 or CYP2D6. Elevated haloperidol concentrations occurring through inhibition of cytochrome P450 pathways may increase the risk of adverse effects, including QT prolongation. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
    Halothane: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Hawthorn, Crataegus laevigata: Hawthorn, Crataegus laevigata (also known as C. oxyacantha) may potentially interact with antihypertensive, heart failure, or arrhythmia medications such as the calcium-channel blockers. Following hawthorn administration, the cardiac action potential duration is increased and the refractory period is prolonged. Hawthorn may also lower peripheral vascular resistance. Patients with hypertension or heart failure should be advised to only use hawthorn with their prescribed medications after discussion with their prescriber. Patients who choose to take hawthorn should receive periodic blood pressure and heart rate monitoring.
    Homatropine; Hydrocodone: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydantoins: Hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers and thereby reduce their oral bioavailability. The dosage requirements of nicardipine may be increased in patients receiving concurrent hydantoin anticonvulsants.
    Hydralazine; Isosorbide Dinitrate, ISDN: Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Hydrochlorothiazide, HCTZ; Metoprolol: Although concomitant therapy with nicardipine and metoprolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), metoprolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Nicardipine has been reported to increase plasma concentrations and oral bioavailability of certain beta-blockers (e.g., metoprolol). Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Hydrochlorothiazide, HCTZ; Propranolol: Although concomitant therapy with nicardipine and propranolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), propranolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Nicardipine has been reported to increase plasma concentrations and oral bioavailability of certain beta-blockers (e.g., propranolol). Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Hydrocodone: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Ibuprofen: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Hydrocodone; Phenylephrine: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Hydrocodone; Potassium Guaiacolsulfonate: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Hydrocodone; Pseudoephedrine: Monitor for respiratory depression, sedation and decreased analgesic effect if hydrocodone and nicardipine are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as nicardipine, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as nicardipine, may result in a reduction in the analgesic effect of hydrocodone. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Ibrutinib: Avoid concomitant use of nicardipine, a strong CYP3A4 inhibitor, with ibrutinib, a CYP3A4 substrate. For short-term (<= 7 days) of nicardipine, consider interrupting ibrutinib therapy until nicardipine is no longer needed. Monitor patients for signs of increased ibrutinib toxicity.
    Ibuprofen lysine: NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs.
    Ibuprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ibuprofen; Oxycodone: Coadministration of nicardipine, a CYP3A4 inhibitor according to in vitro data, and oxycodone, a CYP3A4 substrate, may increase oxycodone plasma concentrations and increase or prolong related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patient for an extended period of time and adjust dosage as necessary; oxycodone dosage adjustments may be needed if the CYP3A4 inhibitor is discontinued. Concurrent administration of oxycodone and voriconazole, another CYP3A4 inhibitor, increased oxycodone AUC by 3.6-fold and the Cmax by 1.7-fold. If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ibuprofen; Pseudoephedrine: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Iloperidone: Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Iloprost: Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Imatinib, STI-571: Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including nicardipine.
    Indinavir: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Indomethacin: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Irinotecan Liposomal: Use caution if irinotecan liposomal is coadministered with nicardipine, a CYP3A4 inhibitor in vitro, due to increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: Nicardipine is a strong P-glycoprotein (P-gp) inhibitor and, in vitro, a moderate inhibitor of CYP3A4; irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isavuconazonium: Concomitant use of isavuconazonium with nicardipine may result in increased serum concentrations of isavuconazonium. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; nicardipine is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Isoflurane: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. Patients should be monitored for loss of antihypertensive effect if rifampin is added to nicardipine therapy.
    Isoniazid, INH; Rifampin: Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. Patients should be monitored for loss of antihypertensive effect if rifampin is added to nicardipine therapy.
    Isoproterenol: The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.
    Isosorbide Dinitrate, ISDN: Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Isosorbide Mononitrate: Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Itraconazole: Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase nicardipine serum concentrations via inhibition of CYP3A4 with the potential for nicardipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and dihydropyridine calcium-channel blockers; therefore, caution is recommmended when administering these medication in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
    Ivabradine: Avoid coadministration of ivabradine and nicardipine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; nicardipine inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: Use caution when administering ivacaftor and nicardipine concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and nicardipine is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
    Ixabepilone: Ixabepilone is a CYP3A4 substrate, and concomitant use with mild or moderate CYP3A4 inhibitors like nicardipine has not been studied. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. Caution is recommended if ixabepilone is coadministered with nicardipine; closely monitor patients for ixabepilone-related toxicities.
    Ketamine: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Ketoconazole: Ketoconazole may decrease the clearance of calcium-channel blockers, such as nicardipine, via inhibition of CYP3A4 metabolism.
    Ketoprofen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ketorolac: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Labetalol: Although concomitant therapy with nicardipine and labetalol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), labetalol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Lacosamide: Lacosamide causes PR interval prolongation in some patients. Caution is advised during coadministration of lacosamide with other drugs that cause PR prolongation, such as calcium-channel blockers, since further PR prolongation is possible. If concurrent use is necessary, an ECG is recommended prior to initiation of lacosamide and after the drug is titrated to the maintenence dose. Patients receiving intravenous lacosamide should be closely monitored due to the potential for profound bradycardia and AV block during coadministration.
    Lanreotide: Lanreotide may cause a decrease in heart rate. Administering drugs that also decrease the heart rate (e.g., calcium-channel blockers) in combination with lanreotide may increase the risk of bradycardia. Dose adjustments of calcium-channel blockers may be necessary.
    Lansoprazole; Naproxen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Lapatinib: Lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1) and is a CYP3A4 substrate. Nicardipine is a P-glycoprotein inhibitor and a weak CYP3A4 inhibitor. Concurrent administration of lapatinib with a P-glycoprotein inhibitor is likely to cause elevated serum lapatinib concentrations, and caution is recommended.
    Levobupivacaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Levodopa: Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Levomilnacipran: Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of nicardipine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Lidocaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Lisdexamfetamine: Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Lithium: Lithium neurotoxicity has been reported during co-administration of lithium and verapamil or diltiazem, and is possible during concurrent use of other calcium-channel blockers with lithium. Symptoms of toxicity have included ataxia, tremors, nausea, vomiting, diarrhea, and tinnitus. The interaction between verapamil and lithium is variable and unpredictable. Both decreased lithium concentrations and lithium toxicity have been reported after the addition of verapamil. The possibility of a loss of lithium's therapeutic effect due to lower serum lithium concentrations may be offset somewhat by the fact that calcium-channel blocking agents share some neuropharmacological actions with lithium; limited data suggest that oral verapamil is effective in controlling an acute manic episode either as a single agent or in combination with lithium. Regarding diltiazem, although neurotoxicity was reported after the addition of diltiazem, other drugs were administered concomitantly. Worsened psychosis has been reported with the combination of diltiazem and lithium. Until more data are available, diltiazem and verapamil should be used cautiously in patients receiving lithium.
    Loperamide: The plasma concentration of loperamide, a CYP3A4, CYP2C8, CYP2D6, and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with nicardipine, an inhibitor of CYP3A4, CYP2C8, CYP2D6, and P-gp. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: The plasma concentration of loperamide, a CYP3A4, CYP2C8, CYP2D6, and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with nicardipine, an inhibitor of CYP3A4, CYP2C8, CYP2D6, and P-gp. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Loratadine; Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Lovastatin: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including lovastatin.
    Lovastatin; Niacin: Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including lovastatin.
    Lumacaftor; Ivacaftor: Use caution when administering ivacaftor and nicardipine concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and nicardipine is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
    Lurasidone: Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known. Also, because lurasidone is primarily metabolized by CYP3A4, concurrent use of CYP3A4 inhibitors, such as nicardipine, can theoretically lead to an increased risk of lurasidone-related adverse reactions.
    Maraviroc: Use caution if coadministration of maraviroc with nicardipine is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A/P-glycoprotein (P-gp) substrate and nicardipine is a CYP3A4/P-gp inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Meclizine: Meclizine is metabolized by CYP2D6, nicardipine is a CYP2D6 inhibitor. Concomitant use may increase meclizine plasma concentrations which may intensify its sedative and anticholinergic effects.
    Meclofenamate Sodium: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Mefenamic Acid: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Mefloquine: Mefloquine is metabolized by CYP3A4. Nicardipine is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
    Melatonin: Melatonin may impair the efficacy of some calcium-channel blockers, and caution is advised with concurrent use. In one placebo-controlled study, melatonin evening ingestion led to significant increases in blood pressure (6.5 mmHg systolic and 4.9 mmHg diastolic) and heart rate (3.9 bpm) throughout the day in patients taking nifedipine (GITS formulation). Melatonin appeared to antagonize the antihypertensive effects of nifedipine. The mechanism of this interaction is unclear. It may be prudent to avoid melatonin use during calcium-channel blocker therapy.
    Meloxicam: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Mephobarbital: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Mepivacaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Mepivacaine; Levonordefrin: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Mestranol; Norethindrone: Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.
    Metformin; Repaglinide: Repaglinide is partly metabolized by CYP3A4 and CYP2C8. Drugs that inhibit these enzymes may increase plasma concentrations of repaglinide. In vitro data indicate that nicardipine is an inhibitor of both CYP3A4 and CYP2C8. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Metformin; Saxagliptin: Monitor patients for hypoglycemia if saxagliptin and nicardipine are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as nicardipine.
    Methadone: Nicardipine, a CYP3A4 inhibitor can theoretically inhibit hepatic metabolism of some opiate agonists, CYP3A4 substrates, such as methadone.
    Methamphetamine: Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium channel blockers. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Methohexital: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Methoxsalen: Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylergonovine: Because of its potential to cause coronary vasospasm, methylergonovine could theoretically antagonize the therapeutic effects of calcium-channel blockers. In addition, calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of methylergonovine and increase the risk of ergot toxicity.
    Methylphenidate: Methylphenidate reduces the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial co-administration and after dosage increases of methylphenidate.
    Methysergide: Because of the potential to cause coronary vasospasm , methysergide theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, verapamil, may also reduce the hepatic metabolism of selected ergot alkaloids and increase the risk of ergot toxicity.
    Metoprolol: Although concomitant therapy with nicardipine and metoprolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), metoprolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Nicardipine has been reported to increase plasma concentrations and oral bioavailability of certain beta-blockers (e.g., metoprolol). Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Midazolam: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including midazolam.
    Mifepristone, RU-486: Mifepristone, RU-486 inhibits CYP3A4 and coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates, including calcium-channel blockers.
    Milnacipran: Milnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents may be diminished during concurrent use of milnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Milrinone: Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mivacurium: Calcium-channel blockers may prolong neuromuscular blockade.
    Nabumetone: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Nadolol: Although concomitant therapy with nicardipine and nadolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), nadolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Nanoparticle Albumin-Bound Paclitaxel: Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like nicardipine. These patients may require additional monitoring and information.
    Naproxen: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Naproxen; Pseudoephedrine: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Naproxen; Sumatriptan: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Nebivolol: Although concomitant therapy with nicardipine and nebivolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), nebivolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Nebivolol; Valsartan: Although concomitant therapy with nicardipine and nebivolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), nebivolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Nefazodone: Caution should be used when CYP3A4 inhibitors, such as nefazodone, are co-administered with nicardipine, a CYP3A4 substrate and inhibitor.
    Nelfinavir: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Nesiritide, BNP: The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Neuromuscular blockers: Calcium-channel blockers may prolong neuromuscular blockade.
    Nevirapine: Nevirapine is an inducer of the cytochrome P4503A enzyme. Concomitant administration of nevirapine with drugs that are extensively metabolized by this enzyme, including calcium-channel blockers may require dosage adjustments.
    Niacin, Niacinamide: Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Niacin; Simvastatin: Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including simvastatin.
    Nilotinib: The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and nicardipine, a substrate and inhibitor of CYP3A4 and a P-gp inhibitor, may result in increased nilotinib and/or nicardipine levels. A nilotinib and/or nicardipine dose reduction may be necessary if these drugs are used together. Monitor patients for nilotinib and/or nicardipine toxicity (e.g., QT interval prolongation, hypotension) if these drugs are used together.
    Nintedanib: In vitro, nicardipine is a potent inhibitor of P-glycoprotein (P-gp) and a moderate CYP3A4 inhibitor; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of nicardipine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nitrates: Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Nitroglycerin: Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Nitroprusside: Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
    Nonsteroidal antiinflammatory drugs: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Octreotide: Dose adjustments in drugs such as beta-blockers and calcium-channel blockers which cause bradycardia and/or affect cardiac conduction may be necessary during octreotide therapy due to additive effects.
    Olanzapine: Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olaparib: Avoid the coadministration of olaparib with nicardipine due to the risk of increased olaparib-related adverse reactions; if concomitant use is necessary, decrease the dose of olaparib to 200 mg by mouth twice daily. Olaparib is a CYP3A4 substrate and nicardipine is a moderate CYP3A4 inhibitor in vitro. Additionally, nicardipine is a strong in vitro inhibitor of P-glycoprotein (P-gp); olaparib is an in vitro P-gp substrate, although the clinical relevance is unknown. Simulations have suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of olaparib by 2.2-fold and 1.2-fold, respectively.
    Ombitasvir; Paritaprevir; Ritonavir: Elevated plasma concentrations and an increased risk of serious adverse events may occur with coadministration of nicardipine and dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir and nicardipine both prolong the PR interval and the manufacturer for ritonavir recommends caution during coadministration. The metabolic interactions that may occur are complex, with increased plasma concentrations and, thus, adverse reactions of all 5 drugs anticipated. Nicardipine is a CYP2C8 inhibitor, a CYP2D6 potent inhibitor, a CYP3A4 substrate/ inhibitor, and a P-glycoprotein (P-gp) transport substrate/potent inhibitor. Ritonavir is a CYP2D6 substrate/inhibitor, a CYP3A4 substrate/potent inhibitor, and a P-gp substrate/inhibitor. Paritaprevir is a substrate of CYP3A4 and P-gp. Dasabuvir is a substrate of CYP2C8, CYP3A4, and P-gp. Ombitasvir is a P-gp substrate. Caution and close monitoring are advised if these drugs are administered together. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Osimertinib: Use caution if coadministration of osimertinib and nicardipine is necessary, due to the risk of increased osimertinib exposure; if concomitant use is necessary, monitor for osimertinib-related adverse reactions. Osimertinib is a CYP3A substrate and an in vitro substrate of P-glycoprotein (P-gp); in vitro, nicardipine is a CYP3A inhibitor and a strong inhibitor of P-gp. Based on a pharmacokinetic study, CYP3A4 inhibition is not expected to influence the pharmacokinetics of osimertinib; however, P-gp inhibition by nicardipine may result in increased osimertinib exposure.
    Oxaprozin: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Oxycodone: Coadministration of nicardipine, a CYP3A4 inhibitor according to in vitro data, and oxycodone, a CYP3A4 substrate, may increase oxycodone plasma concentrations and increase or prolong related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patient for an extended period of time and adjust dosage as necessary; oxycodone dosage adjustments may be needed if the CYP3A4 inhibitor is discontinued. Concurrent administration of oxycodone and voriconazole, another CYP3A4 inhibitor, increased oxycodone AUC by 3.6-fold and the Cmax by 1.7-fold.
    Paclitaxel: Paclitaxel is a substrate of CYP2C8 and 3A4; in vitro, nicardipine is a moderate inhibitor of both CYP2C8 and 3A4. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
    Paliperidone: Paliperidone may cause orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses of paliperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Pancuronium: Calcium-channel blockers may prolong neuromuscular blockade.
    Paricalcitol: Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as nicardipine. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
    Pasireotide: Pasireotide may cause a decrease in heart rate. Closely monitor patients who are also taking drugs associated with bradycardia such as calcium-channel blockers. Dose adjustments of calcium-channel blockers may be necessary.
    Pazopanib: Avoid administering pazopanib with strong CYP3A4 and P-gp inhibitors, such as nicardipine. Pazopanib is a substrate for CYP3A4, CYP2C8, and P-glycoprotein (P-gp). Nicardipine is an inhibitor of CYP3A4, CYP2C8, and P-gp. Concurrent administration of nicardipine and pazopanib may result in increased pazopanib concentrations.
    Penbutolol: Although concomitant therapy with nicardipine and penbutolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), penbutolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Pentobarbital: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Pentoxifylline: Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
    Phenelzine: Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Phenobarbital: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Phenylephrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Phenylephrine; Promethazine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Phenytoin: Hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers and thereby reduce their oral bioavailability. The dosage requirements of nicardipine may be increased in patients receiving concurrent hydantoin anticonvulsants.
    Photosensitizing agents: Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Pimozide: Concurrent use of pimozide and nicardipine is contraindicated. Pimozide is primarily metabolized through CYP3A4, and to a lesser extent, CYP2D6. Nicardipine is a potent CYP2D6 inhibitor and moderate CYP3A4 inhibitor. Elevated pimozide concentrations occurring through inhibition of CYP3A4 and/or CYP2D6 can lead to QT prolongation, ventricular arrhythmia, and sudden death.
    Pindolol: Although concomitant therapy with nicardipine and pindolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), pindolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Piroxicam: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Posaconazole: Theoretically, posaconazole may inhibit the metabolism of many calcium-channel blockers via inhibition of CYP3A4. Use caution when coadministering posaconazole and any calcium-channel blocker.
    Prazosin: Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used. The use of alpha-blockers with verapamil can lead to excessive hypotension; In addition, verapamil has been reported to increase the AUC and Cmax of prazosin.
    Prilocaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Prilocaine; Epinephrine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Primidone: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Procainamide: Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
    Procaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Propafenone: Certain calcium-channel blockers, such as nicardipine, inhibit CYP3A4, a partial pathway for propafenone metabolism.
    Propofol: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Propranolol: Although concomitant therapy with nicardipine and propranolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), propranolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Nicardipine has been reported to increase plasma concentrations and oral bioavailability of certain beta-blockers (e.g., propranolol). Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Protease inhibitors: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Pseudoephedrine: The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by calcium-channel clockers.
    Quazepam: CYP3A4 inhibitors, such as nicardipine, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity.
    Quetiapine: The cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine. Nicardipine may increase plasma concentrations of quetiapine through CYP3A4 inhibition. The manufacturer of quetiapine recommends a reduced dosage during concurrent administration of CYP3A4 inhibitors.
    Quinidine: Quinidine concentrations decrease by 20 to 40% when nicardipine is added and rise after nicardipine is withdrawn. Although this appears to be an idiosyncratic reaction, quinidine doses may need to be adjusted when nicardipine is added or withdrawn. Careful monitoring of serum quinidine concentrations is prudent following the addition or discontinuation of nicardipine.
    Quinine: Quinine is a substrate of P-glycoprotein (PGP) and nicardipine is a PGP inhibitor; therefore, quinine concentrations could be increased with coadministration. Monitor patients for increased adverse effects of quinine if these drugs are given together.
    Ranitidine: Ranitidine may increase nicardipine AUC by inhibiting hepatic metabolism of nicardipine. Clinicians should be alert for exaggerated nicardipine effects if ranitidine is added to the regimen.
    Ranolazine: Coadministration of ranolazine with nicardipine may lead to an increase in serum levels of ranolazine.
    Rapacuronium: Calcium-channel blockers may prolong neuromuscular blockade.
    Rasagiline: Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider during concurrent use of an MAOI and a calcium-channel blocker.
    Remifentanil: The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving calcium-channel blockers due to additive hypotensive effects.
    Repaglinide: Repaglinide is partly metabolized by CYP3A4 and CYP2C8. Drugs that inhibit these enzymes may increase plasma concentrations of repaglinide. In vitro data indicate that nicardipine is an inhibitor of both CYP3A4 and CYP2C8. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Rifabutin: Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as nicardipine and thereby reduce their oral bioavailability. The dosage requirements of nicardipine may be increased in patients receiving concurrent enzyme inducers.
    Rifampin: Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. Patients should be monitored for loss of antihypertensive effect if rifampin is added to nicardipine therapy.
    Rifapentine: Rifapentine, a CYP3A4 enzyme inducer, may reduce of the oral bioavailability of some calcium channel blockers, including nicardipine. Patients should be monitored for loss of antihypertensive effect if rifapentine is added to nicardipine therapy.
    Rifaximin: Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and nicardipine, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Rilpivirine: Close clinical monitoring is advised when administering nicardipine with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nicardipine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Risperidone: Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Ritonavir: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Rituximab: Patients should not take antihypertensive agents 12 hours prior to rituximab infusions due to the possibility of hypotension occurring during the rituximab infusion.
    Rivaroxaban: The coadministration of rivaroxaban and nicardipine should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. In vitro, nicardipine is a combined CYP3A4 and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
    Rocuronium: Calcium-channel blockers may prolong neuromuscular blockade.
    Rofecoxib: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Romidepsin: Romidepsin is a substrate for CYP3A4 and P-glycoprotein (Pgp). Nicardipine is an inhibitor of CYP3A4 and a strong inhibitor of Pgp. Concurrent administration of romidepsin with an inhibitor of CYP3A4 and Pgp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Ropivacaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Diltiazem and verapamil may also inhibit the CYP3A4-mediated metabolism of levobupivacaine and bupivacaine.
    Ruxolitinib: Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as nicardipine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Saquinavir: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Saxagliptin: Monitor patients for hypoglycemia if saxagliptin and nicardipine are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as nicardipine.
    Secobarbital: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Selegiline, Transdermal: Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Selegiline: Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Selexipag: Coadminister selexipag and nicardipine with caution. Selexipag is a substrate of CYP2C8, and in vitro data indicate nicardipine inhibits CYP2C8. Coadministration may result in an increase in exposure to selexipag and its active metabolite.
    Sevoflurane: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Sibutramine: Sibutramine may raise blood pressure or heart rate. Patients who are controlled on antihypertensive agents should be monitored for changes in blood pressure while taking sibutramine.
    Sildenafil: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as sildenafil.
    Silodosin: During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents. Silodosin is extensively metabolized by CYP450 3A4 and is a substrate for P-glycoprotein (P-gp). In theory, antihypertensive drugs that inhibit CYP3A4 such as diltiazem, verapamil, and nicardipine may cause significant increases in silodosin plasma concentrations. Verapamil may also interact with silodosin through its effects as a P-gp inhibitor.
    Simeprevir: Coadministration of orally administered nicardipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased nicardipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Simvastatin: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including simvastatin.
    Simvastatin; Sitagliptin: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including simvastatin.
    Sincalide: Sincalide-induced gallbladder ejection fraction may be affected by calcium-channel blockers. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of results.
    Sirolimus: Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including sirolimus.
    Sofosbuvir; Velpatasvir: Use caution when administering velpatasvir with nicardipine. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); nicardipine is a potent inhibitor of P-gp. Nicardipine is also an in vitro inhibitor of the hepatic enzymes CYP3A4 and CYP2C8. Velpatasvir is a substrate of both enzymes.
    Sotalol: Although concomitant therapy with nicardipine and sotalol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), sotalol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    St. John's Wort, Hypericum perforatum: St. John's wort appears to induce the metabolism of the calcium-channel blockers, such as nicardipine, apparently by the induction of the CYP3A4 isoenzyme leading to reduced clinical efficacy. The metabolism of calcium channel blockers may also be increased.
    Streptogramins: Dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme, including nicardipine.
    Succinylcholine: Calcium-channel blockers may prolong neuromuscular blockade.
    Sufentanil: The incidence and degree of bradycardia and hypotension during induction with sufentanil may be increased in patients receiving calcium-channel blockers. In addition to additive hypotensive effects, calcium-channel blockers that are CYP3A4 inhibitors (e.g., diltiazem, nicardipine, and verapamil) can theoretically decrease hepatic metabolism of some opiates (CYP3A4 substrates), such as sufentanil.
    Sulindac: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Sunitinib: Concurrent administration of sunitinib with inhibitors of cytochrome P450 3A4 such as nicardipine results in increased concentrations of sunitinib and its primary active metabolite. Whenever possible selection of an alternative concomitant medication with no or minimal enzyme inhibition potential is recommended. If an alternative therapy is not available, monitor patients closely for increased adverse reactions to sunitinib; a reduction in the dose of sunitinib may be required.
    Tacrolimus: Coadministration of nicardipine and tacrolimus may result in elevated plasma tacrolimus concentrations. Monitor plasma concentrations of tacrolimus closely, and adjust the dose as necessary. Tacrolimus is metabolized by CYP3A4; nicardipine is an inhibitor of CYP3A4.
    Tamoxifen: Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as nicardipine. Consider avoiding concomitant use of nicardipine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Tamsulosin: The concomitant administration of tamsulosin with other antihypertensive agents can cause additive hypotensive effects. In addition, diltiazem, nicardipine, and verapamil may increase tamsulosin plasma concentrations via CYP3A4 inhibition. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Telaprevir: Close clinical monitoring is advised when administering nicardipine with telaprevir due to increased potential for nicardipine-related adverse events. When used in combination, the plasma concentrations of nicardipine were increased. If nicardipine dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment.
    Telithromycin: Telithromycin, a ketolide antibiotic, can theoretically compete with nicardipine for metabolism by CYP3A4. This can result in increased concentrations of nicardipine if the two drugs are coadministered.
    Temsirolimus: Use caution if coadministration of temsirolimus with nicardipine is necessary, and monitor for an increase in temsirolimus-related adverse reactions. Temsirolimus is a CYP3A4 substrate and nicardipine is a moderate CYP3A4 inhibitor in vitro. The manufacturer of temsirolimus recommends a dose reduction if coadministered with a strong CYP3A4 inhibitor, but recommendations are not available for concomitant use of moderate inhibitors. Coadministration of temsirolimus with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively; pharmacokinetics. Additionally, temsirolimus is an in vitro substrate of P-glycoprotein (P-gp) and nicardipine is a strong P-gp inhibitor. Concomitant use may result in increased plasma concentrations of temsirolimus (and active metabolite, sirolimus).
    Tenofovir Alafenamide: Close clinical monitoring is advised when administering nicardipine with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Nicardipine is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: Caution is advised when administering tenofovir, a P-gp substrate, concurrently with inhibitors of P-gp, such as nicardipine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Terbinafine: Due to the risk for terbinafine related adverse effects, caution is advised when coadministering nicardipine. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C8, CYP2C19, and CYP3A4; nicardipine is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered.
    Tetrabenazine: Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypretensive agents such as nicardipine. Additionally, nicardipine is a strong inhibitor of CYP2D6. The primary metabolites of tetrabenazine, alpha-dihydrotetrabenzaine (alpha-HTBZ) and beta-dihydrotetrabenazine (beta-HTBZ), are substrates for CYP2D6. Increased alpha-HTBZ and beta-HTBZ serum concentrations may occur during coadministration with nicardipine, leading to an increased risk of tetrabenazine-related adverse reactions. When tetrabenazine is given with a strong inhibitor of CYP2D6, the maximum single dose of tetrabenazine should not exceed 25 mg and the daily dose should not exceed 50 mg.
    Tetracaine: Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
    Thalidomide: Thalidomide and other agents that slow cardiac conduction such as calcium-channel blockers should be used cautiously due to the potential for additive bradycardia.
    Thiopental: Patients should be monitored for loss of antihypertensive effect if CYP3A4 enzyme inducers like the barbiturates are added to nicardipine therapy. Rifampin is a potent hepatic enzyme inducer and has been shown to exert a substantial reduction of the oral bioavailability of some calcium channel blockers. This interaction should be considered with other potent CYP3A4 inhibitors including the barbiturates.
    Thiothixene: Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Ticagrelor: Coadministration of ticagrelor and nicardipine may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and nicardipine is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Tigecycline: Coadministration of P-glycoprotein (P-gp) inhibitors, such as nicardipine, may increase tigecycline serum concentrations. Based on an in vitro study, tigecycline is a P-gp substrate; however, the potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known.
    Timolol: Although concomitant therapy with nicardipine and timolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), timolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Tipranavir: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Tolmetin: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Tolvaptan: Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Nicardipine is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Topotecan: Avoid the concomitant use of nicardipine, a P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of nicardipine and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Toremifene: Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes. Nicardipine inhibits this isoenzyme and may decrease the metabolism of toremifen.
    Trabectedin: Use caution if coadministration of trabectedin and nicardipine is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, nicardipine is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/metered squared) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Tranylcypromine: The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated.
    Trazodone: Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Treprostinil: Although pharmacokinetic drug interaction studies have not been conducted, coadministration of treprostinil and nicardipine, a cytochrome P450 (CYP) 2C8 enzyme inhibitor, may result in increased treprostinil exposure. Human pharmacokinetic studies with oral treprostinil indicate that coadministration of gemfibrozil, another CYP2C8 inhibitor, results in increased exposure to treprostinil. The manufacturer of oral treprostinil recommends a reduction in the starting dose of oral treprostinil when coadministered with gemfibrozil. The clinical significance of this interaction with orally inhaled or parenteral treprostinil and other CYP2C8 inhibitors is unknown.
    Triazolam: CYP3A4 inhibitors, such as nicardipine, may reduce the metabolism of triazolam and increase the potential for benzodiazepine toxicity.
    Tubocurarine: Calcium-channel blockers may prolong neuromuscular blockade.
    Ulipristal: Ulipristal is a substrate of CYP3A4 and nicardipine is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Valdecoxib: If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Vardenafil: Vardenafil is metabolized by hepatic cytochrome P450 3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4, such as nicardipine, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.
    Vecuronium: Calcium-channel blockers may prolong neuromuscular blockade.
    Vemurafenib: Concomitant use of vemurafenib and nicardipine may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 and P-glycoprotein (PGP) substrate and nicardipine is a CYP3A4 and PGP inhibitor. Use caution and monitor patients for increased side effects.
    Venetoclax: Avoid the concomitant use of venetoclax and nicardipine. Venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and may be a P-gp inhibitor at therapeutic dose levels in the gut; nicardipine is an inhibitor of CYP3A4 (in vitro) and P-gp and a P-gp substrate (in vitro). Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day) and consider administering nicardipine at least 6 hours before venetoclax. If nicardipine is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Vilazodone: Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, concurrent use of CYP3A4 inhibitors, such as nicardipine, can theoretically lead to an increased risk of vilazodone-related adverse reactions. However, no dosage adjustment is recommended when vilazodone is co-administered with mild CYP3A4 inhibitors.
    Vinblastine: Nicardipine is an inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1) and a weak inhibitor of cytochrome P450 (CYP) isoenzyme 3A4. Vinblastine is a P-glycoprotein and CYP3A4 substrate. Increased concentrations of vinblastine are likely if it is coadministered with nicardipine; exercise caution.
    Vincristine Liposomal: Avoid the concomitant use of nicardipine and vincristine. Vincristine is a substrate for P-glycoprotein (P-gp). Agents that strongly inhibit P-glycoprotein (P-gp) such as nicardipine will likely alter the pharmacokinetics or pharmacodynamics of vincristine. The toxicity of vincristine could be increased.
    Vincristine: Avoid the concomitant use of nicardipine and vincristine. Vincristine is a substrate for P-glycoprotein (P-gp). Agents that strongly inhibit P-glycoprotein (P-gp) such as nicardipine will likely alter the pharmacokinetics or pharmacodynamics of vincristine. The toxicity of vincristine could be increased.
    Vinorelbine: Nicardipine is a weak inhibitor of CYP3A4 isoenzymes. Coadministration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates such as vinorelbine.
    Vorapaxar: Use caution during concurrent use of vorapaxar and nicardipine. Vorapaxar is a CYP3A4 substrate. Nicardipine inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with nicardipine. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: Voriconazole may inhibit the metabolism of many calcium-channel blockers via inhibition of CYP3A4. Although clinical data are lacking, it may be prudent to exercise caution when co-administering voriconazole and any calcium-channel blocker. Monitor patients heart rate and blood pressure.
    Vortioxetine: Concurrent use of nicardipine and vortioxetine may result in increased plasma concentrations of vortioxetine due to CYP2D6 inhibition by nicardipine. Because the primary isoenzyme involved in the metabolim of vortioxetine is CYP2D6, the manufacturer recommends a reduction in the vortioxetine dose by one-half during co-administration with strong inhibitors of CYP2D6. The vortioxetine dose should be increased to the original level when the CYP2D6 inhibitor is discontinued.
    Yohimbine: Yohimbine (a selective central alpha 2-adrenoceptor antagonist) can increase blood pressure, and therefore can antagonize the therapeutic action of antihypertensive drugs in general. One study in patients with essential hypertension (n = 25) reported an average rise of 5 mmHg in mean blood pressure and a 66% increase in plasma norepinephrine (NE) concentrations following yohimbine administration (4 x 5.4 mg tablets PO). Use with particular caution in hypertensive patients with high or uncontrolled BP.
    Zafirlukast: Caution should be used when CYP3A4 inhibitors, such as zafirlukast are co-administered with nicardipine, a CYP3A4 substrate and inhibitor. Zafirlukast may inhibit the metabolism and increase the effect of nicardipine.
    Zileuton: Zileuton is a CYP3A4 inhibitor and may decrease the metabolism and increase the effect of nicardipine.
    Ziprasidone: Nicardipine is a weak inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of ziprasidone, a CYP3A4 substrate.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, nicardipine is minimally excreted into human milk. Among 18 infants exposed to nicardipine through breast milk in the post-partum period, the calculated daily infant dose was less than 0.3 mcg or between 0.015 to 0.004% of the therapeutic dose in a 1 kg infant; no adverse events were observed. The American Academy of Pediatrics (AAP) has not evaluated the use of nicardipine in breast-feeding mothers; however, the AAP regards nifedipine, a related medication, as usually compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Similar to nifedipine, nicardipine inhibits the influx of extracellular calcium across the cell membranes of myocardial and vascular smooth muscle without altering serum calcium concentrations and inhibits intracellular phosphodiesterase. Unlike nifedipine, however, nicardipine has greater selectivity for vascular smooth muscle than for cardiac muscle. Thus, nicardipine relaxes the peripheral vasculature without affecting inotropy. While verapamil and diltiazem exert balanced effects on calcium channels in the SA node, AV node, and vasculature, nicardipine and other members of the dihydropyridine group predominantly act on the vasculature, making these agents more potent peripheral vasodilators.The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries. These effects elicit an increased oxygen delivery to the myocardial tissue, and a decreased total peripheral resistance, systemic blood pressure, and afterload. Although originally it was believed that these drugs improved oxygen supply, it now appears that their effectiveness as anti-ischemic agents arises from their ability to alter the systemic balance between supply and demand. Reduced afterload and reduced myocardial wall tension lead to reduced myocardial oxygen demand, which now seems to best explain the benefit of nicardipine and other dihydropyridines in the treatment of angina. Thus, nicardipine increases myocardial oxygen supply (secondary to coronary vasodilation) and also decreases myocardial oxygen demand (secondary to decreased afterload). Nicardipine appears particularly effective in treating variant angina (i.e., vasospastic angina) due to this ability to increase myocardial oxygen supply by inducing coronary vasodilation. The efficacy of nicardipine in patients with chronic stable angina, on the other hand, is related to the decrease in myocardial oxygen demand secondary to decreased afterload.Nicardipine has no effect on the atrioventricular (AV) or sinoatrial nodal cardiac conduction systems. Negative inotropic effects rarely are noted clinically, presumably due to a reflex increase in heart rate in response to nicardipine's vasodilatory activity as well as a negligible effect on myocardial contractility. Nicardipine therapy usually does not affect hemodynamic parameters in patients with normal ventricular function, although patients with decreased left ventricular function can experience an increase in ejection fraction and a decrease in left ventricular filling pressures. Nicardipine equals or exceeds nifedipine as an arterial and coronary artery vasodilator, with its vasodilatory effects being more pronounced in hypertensive than in normotensive patients. In general, calcium-channel blockers exert favorable effects on LVH, and do not worsen insulin resistance or exert detrimental effects on the lipid profile.

    PHARMACOKINETICS

    Nicardipine is administered orally and intravenously. Greater than 95% of nicardipine is protein bound to alpha1-acid glycoproteins, albumin, and lipoproteins; protein binding is pH dependent and increases with increased serum pH. Nicardipine also binds to erythrocytes. Volume of distribution is 8.3 L/kg in adult patients. Extensive hepatic metabolism of nicardipine via the CYP450 pathway causes the formation of inactive metabolites, which are glucuronidated and eliminated primarily via renal (60%) and fecal (35%) routes. Less than 1% of unchanged drug is excreted in the urine.
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP2D6, CYP2C19, CYP2C8, P-gp
    Nicardipine is rapidly and extensively metabolized by CYP2C8, CYP2D6, and CYP3A4. While it does not induce or inhibit its own metabolism, nicardipine is a strong inhibitor of CYP2D6 and also inhibits the CYP2C19, CYP3A4, and CYP2C8. In addition, nicardipine is a substrate and inhibitor of P-glycoprotein (P-gp).

    Oral Route

    Nicardipine is rapidly and completely absorbed after oral administration but undergoes extensive first-pass metabolism, resulting in a bioavailability of about 35%. Oral nicardipine pharmacokinetics are nonlinear due to saturable first-pass metabolism.
     
    Immediate-release formulations
    Peak plasma concentrations occur 30 to 120 minutes (mean Tmax = 60 minutes) after administration of immediate-release nicardipine. In pharmacokinetic studies of adult patients, steady state Cmax after 20 mg, 30 mg, and 40 mg doses every 8 hours averaged 36 ng/mL, 88 ng/mL, and 133 ng/mL, respectively. Increasing the dose from 20 mg to 30 mg more than doubled Cmax, while increasing the dose from 20 mg to 40 mg increased the Cmax more than 3-fold. Disproportionate increases in AUC were also observed. Pharmacokinetics after drug absorption are also nonlinear. In adult patients, half-life over the first 8 hours after oral administration is 2 to 4 hours; mean terminal half-life is 8.6 hours. The bioavailability of nicardipine is reduced when administered with food; mean Cmax and AUC are 20% to 30% lower than those of fasting subjects when given 1 to 3 hours after a high fat meal.
     
    Extended-release formulations
    Bioavailability of extended-release nicardipine is somewhat lower than that of immediate-release nicardipine, except when given at the highest dose. Peak plasma concentrations occur 1 to 4 hours after administration of the extended-release formulation. When compared to an equivalent daily dose of immediate-release nicardipine, Cmin is similar while Cmax is significantly reduced, hence a reduction in plasma concentration fluctuation. In pharmacokinetic studies of adult patients, steady state Cmax after 30 mg, 45 mg, and 60 mg doses every 12 hours averaged 13.4 ng/mL, 34 ng/mL, and 58.4 ng/mL, respectively. Doubling the dose increased Cmax 4-fold to 5-fold. Disproportionate increases in AUC were also observed. In adult patients, mean terminal half-life is 8.6 hours. When given with a high fat meal, mean Cmax is 45% lower, AUC is 25% lower, and Cmin is 75% higher than those of fasting subjects.

    Intravenous Route

    Rapid, dose-related increases in plasma concentrations are seen within 2 hours of IV nicardipine infusion initiation. After this, plasma concentrations increase at a slower rate and approach steady state at 24 to 48 hours. Nicardipine plasma concentrations decrease tri-exponentially, with a rapid early distribution phase (alpha half-life = 3 minutes), an intermediate phase (beta half-life = 45 minutes), and slow terminal phase (gamma half-life = 14 hours) that is only seen after long-term IV infusion. Plasma clearance is 0.4 L/kg/hour in adult patients. Duration of action after a single dose of IV nicardipine is approximately 3 hours. After IV infusion discontinuation, plasma concentrations decrease rapidly with at least a 50% reduction within the first 2 hours. The pharmacokinetics of IV nicardipine are linear over the dosage range of 0.5 to 40 mg/hour in adult patients.