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  • CLASSES

    Anti-anginal Agents, other
    Anti-arrhythmics, Class IV
    Benzothiazepine Calcium Channel Blockers

    DEA CLASS

    Rx

    DESCRIPTION

    Oral and IV, benzothiazepine calcium-channel blocker; primarily used for angina, HTN, PST, and ventricular rate control in AFIB; slows AV conduction; vasodilatory properties; less negative inotropic effects than verapamil or nifedipine.

    COMMON BRAND NAMES

    Cardizem, Cardizem CD, Cardizem LA, Cardizem SR, Cartia XT, Dilacor XR, Dilt-CD, Diltia XT, Diltzac, Matzim LA, Taztia XT, Tiazac

    HOW SUPPLIED

    Cardizem CD/Cardizem SR/Cartia XT/Dilacor XR/Dilt-CD/Diltia XT/Diltiazem/Diltiazem Hydrochloride/Diltzac/Taztia XT/Tiazac Oral Cap ER: 60mg, 90mg, 120mg, 180mg, 240mg, 300mg, 360mg, 420mg
    Cardizem LA/Diltiazem/Diltiazem Hydrochloride/Matzim LA Oral Tab ER: 120mg, 180mg, 240mg, 300mg, 360mg, 420mg
    Cardizem/Diltiazem/Diltiazem Hydrochloride Oral Tab: 30mg, 60mg, 90mg, 120mg
    Diltiazem/Diltiazem Hydrochloride Intravenous Inj Pwd F/Sol: 100mg
    Diltiazem/Diltiazem Hydrochloride Intravenous Inj Sol: 1mL, 5mg

    DOSAGE & INDICATIONS

    For the treatment of hypertension.
    Oral dosage (regular-release tablets†)
    Children and Adolescents

    Definitive dosage has not been established. Initial dosages of 1.5 to 2 mg/kg/day PO, given in 3 to 4 divided doses, have been reported. The maximum reported dose for children with hypertension is 6 mg/kg, up to 360 mg, per day.

    Oral dosage (Extended-release once-daily dosage forms; i.e., Cardizem CD capsules, Cardizem LA tablets, Dilacor-XR capsules, Diltia XT capsules, Taztia XT capsules, Tiazac capsules, or generic equivalents)
    Adults

    Initially, 180 to 240 mg PO once daily. Adjust dosage to individual patient needs up to a maximum of 540 mg/day. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, schedule dosage adjustments accordingly. The dosage range studied in clinical trials was 120 to 540 mg. In general, initiate therapy at the lower end of the dosage range in geriatric patients.

    Oral dosage (Cardizem SR sustained-release twice-daily capsules or generic equivalent)
    Adults

    Initially, 60 to 120 mg PO twice daily. Increase dose if necessary. The usual dosage range during clinical studies was 120 to 180 mg PO twice daily. Max: 360 mg/day. In general, initiate therapy at the lower end of the dosage range in geriatric patients.

    For the treatment of chronic stable angina.
    Oral dosage (Regular-release tablets)
    Adults

    Initially, 30 mg PO 4 times per day administered before meals and at bedtime, gradually increasing the dosage at 1- or 2-day intervals until angina is optimally controlled. Maximum daily dose is 360 mg/day PO, given in 3 or 4 divided doses. The usual dosage range is 180 to 360 mg/day.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Some patients respond to a lower dosage; adjust dosage based on clinical response. In geriatric vs. younger subjects, the half-life of diltiazem is prolonged and clearance is decreased.

    Oral dosage (Extended-release once-daily capsules; includes Cardizem CD, Dilacor XR, Diltia XT capsules, Taztia XT capsules, Tiazac, or generic equivalents)
    Adults

    Initially, 120 to 180 mg PO once daily. In general, titrate dosage at 1- to 2-week intervals. Although there is limited clinical experience with doses greater than 360 mg/day, individual patients may respond to higher doses. Maximum dosage is 480 mg/day PO for Cardizem CD and Dilacor XR; the maximum dosage is listed as up to 540 mg/day PO by the manufacturer for Tiazac.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Some patients respond to a lower dosage; adjust dosage based on clinical response. In geriatric vs. younger subjects, the half-life of diltiazem is prolonged and clearance is decreased.

    Oral dosage (Extended-release once-daily tablets; specifically for Cardizem LA)
    Adults

    Initially, 180 mg PO once daily, given either in the morning or evening. In general, titrate dosage at 1- to 2-week intervals. Doses greater than 360 mg/day do not appear to provide additional benefit. Evening doses up to 420 mg/day (Cardizem LA) have been studied in angina patients.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Some patients respond to a lower dosage; adjust dosage based on clinical response. In geriatric vs. younger subjects, the half-life of diltiazem is prolonged and clearance is decreased.

    For the treatment of variant angina (Prinzmetal's angina).
    Oral dosage (Regular-release tablets)
    Adults

    Initially, 30 mg PO 4 times per day administered before meals and at bedtime, gradually increasing the dosage at 1- or 2-day intervals until angina is optimally controlled. The usual dosage range is 180 to 360 mg/day. Maximum daily dose is 480 mg/day, given in 3 or 4 divided doses.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Some patients respond to a lower dosage; adjust dosage based on clinical response. In geriatric vs. younger subjects, the half-life of diltiazem is prolonged and clearance is decreased.

    Oral dosage (Extended-release once-daily dosage forms; i.e., Cardizem CD capsules or generic equivalent)
    Adults

    Initially, 120 to 180 mg PO once daily. There is limited clinical experience with doses greater than 360 mg/day. Maximum dosage is 540 mg/day PO.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Some patients respond to a lower dosage; adjust dosage based on clinical response. In geriatric vs. younger subjects, the half-life of diltiazem is prolonged and clearance is decreased.

    For the treatment of paroxysmal supraventricular tachycardia (PSVT) or control of ventricular rate in atrial flutter or atrial fibrillation.
    For the short-term treatment of rapid ventricular rate secondary to atrial arrhythmias† in adolescents, children, and infants.
    Intravenous dosage (bolus and continuous IV infusion)
    Infants older than 7 months†, Children†, and Adolescents†

    0.25 mg/kg IV over 5 minutes followed by 0.05 to 0.15 mg/kg/hour continuous IV infusion (mean 0.11 mg/kg/hour) has been reported. A retrospective case series reported use of IV diltiazem infusions for 14 to 126 hours to control ventricular rate in 10 patients ages 7 months to 21 years. Prior to diltiazem, the mean atrial and ventricular rates were 275 +/- 50 beats/minute and 184 +/- 55 beats/minute, respectively. After therapy initiation, the mean ventricular rates were 141 +/- 56 at 10 minutes, 118 +/- 41 at 60 minutes, and 108 +/- 28 at 6 hours. The patients' primary arrhythmias were postoperative intraatrial reentrant tachycardia (n = 4), ectopic atrial tachycardia (n = 3), atrial fibrillation (n = 1), multifocal atrial tachycardia (n = 1), and chaotic atrial rhythm (n = 1), and 6 of 10 patients had some form of congenital heart disease.

    For long-term control of ventricular rate in atrial flutter† or atrial fibrillation†.
    Oral dosage (extended-release formulations)
    Adults

    120 to 360 mg PO once daily. Clinical practice guidelines recommend a nondihydropyridine calcium channel blocker to slow the ventricular heart rate in patients with paroxysmal, persistent, or permanent atrial fibrillation. A nondihydropyridine calcium channel blocker is the preferred agent in patients with chronic obstructive pulmonary disease. Avoid use in patients with pre-excitation, left ventricular systolic dysfunction, or decompensated heart failure.

    Intravenous dosage (Bolus dose followed with continuous IV infusion)
    Adults

    0.25 mg/kg (15 to 20 mg is a typical dose) IV bolus over 2 minutes. After 15 minutes, a second bolus dose of 0.35 mg/kg IV (20 to 25 mg is a typical dose) over 2 minutes may be administered, if needed. Some patients may respond to an initial bolus dose of 0.15 mg/kg; however, experience with this dose is limited and the duration of action may be shorter. Subsequent bolus doses should be individualized. Begin 10 mg/hour continuous IV infusion immediately following the IV bolus. Some patients respond to lower doses (e.g., 5 mg/hour). Increase infusion by 5 mg/hour up to a maximum of 15 mg/hour as needed. Continuous IV therapy should not be administered for longer than 24 hours. Clinical practice guidelines recommend an intravenous nondihydropyridine calcium channel blocker to slow the ventricular heart rate in patients with paroxysmal, persistent, or permanent atrial fibrillation in the acute setting in patients without pre-excitation. A nondihydropyridine calcium channel blocker is the preferred agent in patients with chronic obstructive pulmonary disease. Avoid use in patients with left ventricular systolic dysfunction or decompensated heart failure. Clinical practice guidelines for cardiopulmonary resuscitation and emergency cardiovascular care also suggest a nondihydropyridine calcium channel blocker for PSVT if adenosine or vagal maneuvers fail to convert, if PSVT recurs after these therapies, or if these therapies disclose another SVT.

    For the relief of ongoing ischemia in patients with unstable angina† or after acute non-ST-segment elevation myocardial infarction† in the absence of congestive heart failure, pulmonary congestion, left ventricular dysfunction, or AV block, when beta-blockers are ineffective or contraindicated.
    Oral dosage (Regular-release tablets)
    Adults

    Initially, 30 to 60 mg PO 4 times per day. Dosage may be increased up to 360 mg per day, given in 3 to 4 divided doses. Individual patients may respond to higher doses up to 480 mg per day.

    Geriatric

    See adult dosage. In general, initiate dosage selection at the lower end of the adult dosage range. Some patients respond to a lower dosage; adjust dosage based on clinical response. In geriatric versus younger subjects, the half-life of diltiazem is prolonged and clearance is decreased.

    For the treatment of idiopathic dilated cardiomyopathy†.
    Oral dosage (Regular-release tablets)
    Adults

    A dosage regimen of 30 mg PO 3 times daily, titrated to 60 to 90 mg PO 3 times daily, has been studied. In a double-blind, multicenter study, 186 patients with idiopathic dilated cardiomyopathy were randomized to either diltiazem or placebo. All had ejection fractions less than 50% and none had coronary artery disease. After 24 months, survival was similar in the diltiazem and placebo groups. Stroke work index improved and exercise endurance deteriorated less in diltiazem-treated patients.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Some patients respond to a lower dosage; adjust dosage based on clinical response. In geriatric vs. younger subjects, the half-life of diltiazem is prolonged and clearance is decreased.

    For migraine prophylaxis†.
    Oral dosage
    Adults

    Doses of 120 to 360 mg/day PO have been recommended.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Some patients respond to a lower dosage; adjust dosage based on clinical response. In geriatric vs. younger subjects, the half-life of diltiazem is prolonged and clearance is decreased.

    For the treatment of proteinuria† associated with diabetic nephropathy†.
    Oral dosage (Cardizem SR twice-daily sustained-release capsules)

    NOTE: The brand formulation is no longer marketed in the United States; however, generic equivalents are available.

    Adults

    Several trials have evaluated the use of diltiazem sustained-release in patients with proteinuria and diabetic nephropathy. Diltiazem produced a decrease in urinary albumin excretion in each study. The mean dosage range was 90 to 120 mg PO twice daily.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Some patients respond to a lower dosage; adjust dosage based on clinical response. In geriatric vs. younger subjects, the half-life of diltiazem is prolonged and clearance is decreased.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    480 mg/day PO for hypertension for most formulations; 540 mg/day PO for hypertension for once-daily extended-release formulations (e.g., Dilacor-XR capsules, Tiazac capsules, Cardizem CD capsules, Cardizem LA tablets).

    Elderly

    480 mg/day PO for hypertension for most formulations; 540 mg/day PO for hypertension for once-daily extended-release formulations (e.g., Dilacor-XR capsules, Tiazac capsules, Cardizem CD capsules, Cardizem LA tablets).

    Adolescents

    Safety and efficacy have not been established; doses of 6 mg/kg (up to 360 mg) per day PO have been used off-label for hypertension.

    Children

    Safety and efficacy have not been established; doses of 6 mg/kg (up to 360 mg) per day PO have been used off-label for hypertension.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Consider dose reduction in patients with hepatic impairment, since hepatic impairment significantly increases diltiazem half-life and bioavailability. Adjust the dosage based on clinical response.

    Renal Impairment

    No dosage adjustment is needed.
     
    Intermittent hemodialysis
    Diltiazem is not significantly removed by hemodialysis.

    ADMINISTRATION

    NOTE: Oral diltiazem is marketed in several different dosage forms. The dosages and indications for these agents are not identical.
     

    Oral Administration

    Do not significantly increase grapefruit juice intake while taking diltiazem, or avoid grapefruit juice if possible.

    Oral Solid Formulations

    Diltiazem direct compression tablets: Administer before meals and at bedtime. Swallow whole; do not split, crush, or chew the tablets; per the labeled instructions to patients, the medication is formulated to slowly release.
    Cardizem CD or equivalent (Cartia XT) generic extended-release capsules 24 hours: Administered once-daily; may be administered without regard to meals.
    Cardizem LA extended-release tablets 24 hours: Administered once-daily (morning or evening); may be administered without regard to meals.
    Cardizem SR extended-release capsules 12 hours or generic equivalents: NOTE: The brand formulation is no longer marketed in the US; however, generics are available. Was administered twice-daily, may be administered without regard to meals.
    Dilacor XR or generic equivalent (Diltia XT) extended-release capsules 24 hours: Administered once-daily. Take on an empty stomach. Swallow whole, do not open, cut, chew, or crush.
    Tiazac or generic equivalent (Taztia XT) extended-release capsules 24 hours: Administered once-daily; may be administered without regard to meals. Do not subdivide the contents of a capsule; the capsule contents must be administered in their entirety. The capsule may be administered by opening the capsule and sprinkling the capsule contents onto a spoonful of applesauce. The applesauce should not be hot. The applesauce mixture should be swallowed immediately, and then followed with a glass of water.

    Extemporaneous Compounding-Oral

    Extemporaneous Oral Suspension Preparation†
    NOTE: The product labeling states that diltiazem tablets should not be crushed. However, an extemporaneously prepared suspension made from diltiazem tablets (Lederle Laboratories, expiration Aug. 1995) has been reported ; this recipe has been used in clinical practice, particularly for patients requiring small doses (e.g., young children). Monitor the patient's blood pressure closely when using the compounded formulation. The Michigan Pediatric Safety Collaboration recommends using a standard concentration of 12 mg/mL for compounded oral diltiazem suspension.
     
    The following procedure can be used to prepare 120 mL of a 12 mg/mL suspension :
    Use a mortar and pestle to grind sixteen 90-mg diltiazem hydrochloride regular-release tablets into a fine powder.
    In a separate container, mix 60 mL Ora-Sweet with 60 mL Ora-Plus to be used as the base solution. Alternatively, cherry syrup may be substituted for base solution mixture.
    Add a small amount of the base solution to the fine powder and mix into a uniform paste. Add geometric amounts of the base solution to achieve the almost desired volume while mixing.
    Transfer contents to a graduated cylinder and adjust to a final volume of 120 mL.
    Place in an amber plastic bottle. Shake well before each use.
    Storage: Stable for up to 60 days when stored at 5 degrees C or 25 degrees C (room temperature).

    Injectable Administration

    For intravenous use only.
    Vials are unpreserved, single-use containers. Discard any unused portion of diltiazem after vial entry.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    IV Push
    No dilution necessary.
    Inject dose IV over 2 minutes.
     
    Continuous IV Infusion
    Dilute appropriate dose of injection solution in 0.9% Sodium Chloride, 5% Dextrose, or 5% Dextrose and 0.45% Sodium Chloride to give concentrations of 0.45—1 mg/mL. A common infusion dilution is 125 mg of diltiazem injection added to 100 mL of an appropriate diluent to give a final concentration of 125 mg/125 mL (1 mg/mL).
    For adult patients, infuse at an initial rate of 10 mg/hr, and increase if necessary to 15 mg/hr. Rates greater than 15 mg/hr or infusions longer than 24 hours are not recommended.

    STORAGE

    Generic:
    - Discard product that has been stored at room temperature for over 30 days
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - May be stored at room temperature for up to 1 month
    - Refrigerate (between 36 and 46 degrees F)
    Cardizem:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Cardizem CD:
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Cardizem LA:
    - Avoid excessive humidity
    - Avoid temperatures above 86 degrees F
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Cardizem SR:
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Cartia XT :
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Dilacor XR:
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Dilt-CD :
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Diltia XT:
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Diltzac:
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Matzim LA:
    - Avoid excessive humidity
    - Avoid temperatures above 86 degrees F
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Taztia XT:
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tiazac:
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

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

    Diltiazem can precipitate or exacerbate heart failure or cause excessive bradycardia or cardiac conduction abnormalities in patients with ventricular dysfunction, severe bradycardia, cardiogenic shock, or congestive heart failure and/or patients taking beta-adrenergic blocking agents. Diltiazem is contraindicated in patients with acute myocardial infarction and pulmonary congestion and should not be used in patients with acute myocardial infarction and associated left ventricular dysfunction or congestive heart failure. Further, in patients with cardiogenic shock, intravenous diltiazem is contraindicated.

    Hypotension

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

    AV block

    Due to its inhibitory effects on AV node conduction, diltiazem is contraindicated in patients with preexisting second- or third-degree AV block or previous conduction abnormalities. Diltiazem should be used with extreme caution in patients taking beta-adrenergic blocking agents.

    Sick sinus syndrome

    Diltiazem is contraindicated in patients with sick sinus syndrome (SSS). Use of diltiazem in patients with SSS may lead to severe hypotension, bradycardia, or asystole. Patients with SSS with a functioning artificial ventricular pacemaker may use still use a calcium channel blocker.

    Lown-Ganong-Levine syndrome, ventricular tachycardia, Wolff-Parkinson-White syndrome

    Use of diltiazem for treatment of atrial fibrillation or flutter may precipitate severe ventricular arrhythmias and is contraindicated in patients with Wolff-Parkinson-White syndrome or Lown-Ganong-Levine syndrome. Patients with these reentrant arrhythmias with a functioning artificial ventricular pacemaker may still use  a calcium channel blocker. Do not use the IV formulation in patients with wide-complex ventricular tachycardia as these patients are at risk of developing ventricular fibrillation after intravenous diltiazem.

    Hepatic disease

    Patients with hepatic disease, such as cirrhosis or hepatic failure, can experience a delayed clearance of diltiazem and can be at greater risk for accumulation and toxicity. Diltiazem pharmacokinetics and dosage requirements are not altered by renal impairment.

    Aortic stenosis

    Diltiazem should not be used in advanced aortic stenosis because it can cause a worsening of the abnormal pressure gradient associated with this condition.

    Gastroesophageal reflux disease (GERD), hiatal hernia

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

    Pregnancy

    There are no well-controlled studies of diltiazem in pregnancy. Administer diltiazem to pregnant women only if the potential benefit justifies the potential risk to the fetus. Animal studies involving doses ranging from 5 to 10 times greater than the daily recommended therapeutic dose has resulted in embryo and fetal death. In some studies, skeletal abnormalities have been reported. At doses 20 times the human dose or greater there was an increase incidence of stillbirths.[28277]

    Breast-feeding

    Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If diltiazem therapy is deemed essential to the mother, the manufacturer recommends an alternative method of infant feeding.[28277] However, the American Academy of Pediatrics generally considers the use of diltiazem to be usually compatible with breast-feeding. The AAP also considers verapamil, another calcium-channel blocker, to be usually compatible with breast-feeding.

    Geriatric

    In geriatric versus younger adult subjects, the half-life of diltiazem is prolonged and clearance is decreased, with potential increase in risk for drug accumulation and toxicity. In general, initiate dosage in geriatric patients at the lower end of the adult dosage and adjust dosage based on clinical response. According to the Beers Criteria, non-dihydropyridine calcium channel blockers including diltiazem are considered potentially inappropriate medications (PIMs) for use in geriatric patients with heart failure due to the potential for fluid retention and exacerbation of the condition; however, avoidance is only recommended in heart failure patients with a reduced ejection fraction. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. In addition, calcium channel blockers may cause peripheral edema and clinically significant constipation; some agents may cause generalized aching, headache, and muscle pain. There are many drug interactions that can potentiate the effects of antihypertensives. Some antihypertensives require a gradual taper to avoid adverse consequences caused by abrupt discontinuation. The OBRA guidelines also caution that antiarrhythmic agents can have serious adverse effects (e.g., impairment of mental function, appetite, behavior, heart function, or falls) in older individuals.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 0-3.6
    AV block / Early / 0-3.3
    asystole / Rapid / 0-2.0
    heart failure / Delayed / 0-2.0
    atrial fibrillation / Early / 0-2.0
    atrial flutter / Early / 0-2.0
    GI bleeding / Delayed / 0-2.0
    peptic ulcer / Delayed / 0-2.0
    vasculitis / Delayed / 0-2.0
    retinopathy / Delayed / 0-2.0
    ocular hemorrhage / Delayed / 0-2.0
    renal failure (unspecified) / Delayed / 0-2.0
    ventricular fibrillation / Early / 0-1.0
    ventricular tachycardia / Early / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    exfoliative dermatitis / Delayed / 0-1.0
    acute generalized exanthematous pustulosis (AGEP) / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    angioedema / Rapid / Incidence not known
    hemolytic anemia / Delayed / Incidence not known

    Moderate

    peripheral edema / Delayed / 0-15.0
    dyspnea / Early / 0-6.0
    hypotension / Rapid / 0-4.3
    constipation / Delayed / 0-3.6
    bundle-branch block / Early / 0-2.0
    chest pain (unspecified) / Early / 0-2.0
    angina / Early / 0-2.0
    sinus tachycardia / Rapid / 0-2.0
    palpitations / Early / 0-2.0
    colitis / Delayed / 0-2.0
    confusion / Early / 0-2.0
    peripheral neuropathy / Delayed / 0-2.0
    depression / Delayed / 0-2.0
    hypertonia / Delayed / 0-2.0
    hallucinations / Early / 0-2.0
    amnesia / Delayed / 0-2.0
    hyperuricemia / Delayed / 0-2.0
    hyperglycemia / Delayed / 0-2.0
    gout / Delayed / 0-2.0
    amblyopia / Delayed / 0-2.0
    conjunctivitis / Delayed / 0-2.0
    myopathy / Delayed / 0-2.0
    bone pain / Delayed / 0-2.0
    cystitis / Delayed / 0-2.0
    nephrolithiasis / Delayed / 0-2.0
    vaginitis / Delayed / 0-2.0
    elevated hepatic enzymes / Delayed / 0-1.0
    impotence (erectile dysfunction) / Delayed / 0-1.0
    gingival hyperplasia / Delayed / 0-1.0
    peripheral vasodilation / Rapid / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    dizziness / Early / 0-10.0
    rhinitis / Early / 0-9.6
    headache / Early / 0-8.9
    dyspepsia / Early / 0-6.0
    infection / Delayed / 0-6.0
    pharyngitis / Delayed / 1.4-6.0
    fatigue / Early / 4.8-4.8
    asthenia / Delayed / 0-4.0
    injection site reaction / Rapid / 3.9-3.9
    cough / Delayed / 1.0-3.0
    back pain / Delayed / 1.7-2.9
    myalgia / Early / 0-2.3
    influenza / Delayed / 2.0-2.3
    nausea / Early / 0-2.2
    syncope / Early / 0-2.0
    eructation / Early / 0-2.0
    weight gain / Delayed / 0-2.0
    dysgeusia / Early / 0-2.0
    diarrhea / Early / 0-2.0
    anorexia / Delayed / 0-2.0
    xerostomia / Early / 0-2.0
    abdominal pain / Early / 0-2.0
    flatulence / Early / 0-2.0
    vomiting / Early / 0-2.0
    drowsiness / Early / 0-2.0
    insomnia / Early / 0-2.0
    tinnitus / Delayed / 0-2.0
    paresthesias / Delayed / 0-2.0
    vertigo / Early / 0-2.0
    tremor / Early / 0-2.0
    photosensitivity / Delayed / 0-2.0
    urticaria / Rapid / 0-2.0
    rash / Early / 1.0-2.0
    petechiae / Delayed / 0-2.0
    purpura / Delayed / 0-2.0
    diaphoresis / Early / 0-2.0
    alopecia / Delayed / 0-2.0
    pruritus / Rapid / 0-2.0
    ocular irritation / Rapid / 0-2.0
    arthralgia / Delayed / 0-2.0
    muscle cramps / Delayed / 0-2.0
    arthropathy / Delayed / 0-2.0
    nasal congestion / Early / 0-2.0
    epistaxis / Delayed / 0-2.0
    sinusitis / Delayed / 0-2.0
    dysmenorrhea / Delayed / 0-2.0
    nocturia / Early / 0-2.0
    polyuria / Early / 0-2.0
    flushing / Rapid / 0-1.7
    gynecomastia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with diltiazem is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with diltiazem is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 2.4-fold.
    Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with diltiazem. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Acebutolol: (Moderate) The combination of diltiazem and a beta-blocker, like acebutolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with diltiazem may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Diltiazem is a moderate inhibitor of CYP3A4.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with diltiazem may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Diltiazem is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with diltiazem may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Diltiazem is a moderate inhibitor of CYP3A4.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with diltiazem may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and diltiazem is a CYP3A4 inhibitor.
    Acetaminophen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Acrivastine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Aldesleukin, IL-2: (Moderate) Calcium channel blockers may potentiate the hypotension seen with aldesleukin, IL 2.
    Alemtuzumab: (Moderate) 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: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. If diltiazem is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like diltiazem can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. Diltiazem increases the half-life of alfentanil by 50% and may delay tracheal extubation after anesthesia. If diltiazem is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
    Alfuzosin: (Major) Alfuzosin and diltiazem may have additive vasodilatory actions; concurrent use of these agents can result in hypotension. Alfuzosin is primarily metabolized by the CYP3A4 hepatic enzyme. Diltiazem, a moderately potent CYP3A4 inhibitor, increases the Cmax and AUC of alfuzosin; alfuzosin increases both the Cmax and AUC of diltiazem, however, no changes in blood pressure are reported.
    Aliskiren; Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Alprazolam: (Moderate) Consider a reduced dose of alprazolam is concurrent use of diltiazem is necessary. Coadministration of alprazolam, a CYP3A4 substrate, with diltiazem, a moderate CYP3A4 inhibitor, may result in increased alprazolam exposure.
    Alprostadil: (Minor) 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.
    Amifostine: (Major) Patients receiving calcium-channel blockers should be closely monitored during amifostine infusions due to additive effects. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. If the antihypertensive cannot be stopped for 24 hours before chemotherapy doses of amifostine, patients should not receive amifostine.
    Amiodarone: (Major) Based on the pharmacology of amiodarone and diltiazem, additive effects on cardiac contractility and/or AV conduction are possible. Concurrent use of amiodarone and diltiazem may result in bradycardia and depressed cardiac output; monitor clinical response. In addition, amiodarone is both a substrate and inhibitor of CYP3A4 metabolism, and may potentially interact with diltiazem via CYP3A4 metabolic pathways.
    Amitriptyline; Chlordiazepoxide: (Moderate) Diltiazem could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide.
    Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Atorvastatin: (Major) According to the manufacturer of diltiazem, clinicians should consider use of a non-CYP3A4-metabolized statin (e.g., pitavastatin, pravastatin, rosuvastatin) in combination with diltiazem. Coadministration of atorvastatin 40 mg with diltiazem 240 mg was associated with a higher plasma concentration of atorvastatin. Increased concentrations of atorvastatin are associated with an increased risk of myopathy and rhabdomyolysis. Diltiazem is a CYP3A4 inhibitor; coadministration with atorvastatin (CYP3A4 substrate) may result in increased concentrations of atorvastatin. (Moderate) Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Benazepril: (Moderate) Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Olmesartan: (Moderate) Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Telmisartan: (Moderate) Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Valsartan: (Moderate) Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) 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 crossover 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: (Major) 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 crossover 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: (Major) 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: (Moderate) Amprenavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4. Although drug interaction studies have not been conducted, the serum concentration of diltiazem may be increased with concomitant administration of amprenavir.
    Amyl Nitrite: (Moderate) 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.
    Apalutamide: (Major) Avoid coadministration of diltiazem and apalutamide due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable levels.
    Apixaban: (Moderate) Use apixaban and diltiazem together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with diltiazem. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Apomorphine: (Moderate) 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: (Minor) Apraclonidine had minimal effects on heart rate and blood pressure during clinical studies in patients with glaucoma. However, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Use caution during concurrent use, especially in patients with severe, uncontrolled cardiovascular disease, including hypertension.
    Aprepitant, Fosaprepitant: (Moderate) Avoid the concomitant use of diltiazem with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased diltiazem exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in diltiazem- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Diltiazem is a moderate CYP3A4 inhibitor 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. Diltiazem is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of diltiazem. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, increased aripiprazole blood levels may occur when the drug is coadministered with inhibitors of CYP3A4 such as diltiazem. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor. Due to aripiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.
    Artemether; Lumefantrine: (Moderate) Diltiazem is a substrate/inhibitor and artemether is 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. (Moderate) Diltiazem is a substrate/inhibitor and lumefantrine is 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.
    Asenapine: (Moderate) 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; Codeine: (Moderate) Concomitant use of codeine with diltiazem may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Diltiazem is a moderate inhibitor of CYP3A4.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with diltiazem may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Diltiazem is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with diltiazem may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Diltiazem is a moderate inhibitor of CYP3A4.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with diltiazem may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and diltiazem is a CYP3A4 inhibitor.
    Atazanavir: (Major) Coadministration of atazanavir with diltiazem may result in increased plasma concentrations of either drug. Concurrent atazanavir use led to a 2-fold increase in the AUC of diltiazem. A 50% dose reduction of diltiazem should be considered and ECG monitoring is recommended when diltiazem is used with atazanavir. Additionally, atazanavir can prolong the PR interval, especially with high serum concentrations. Greater lengthening of the PR interval with the combined use of diltiazem and atazanavir as compared to either alone has been documented.
    Atazanavir; Cobicistat: (Major) Coadministration of atazanavir with diltiazem may result in increased plasma concentrations of either drug. Concurrent atazanavir use led to a 2-fold increase in the AUC of diltiazem. A 50% dose reduction of diltiazem should be considered and ECG monitoring is recommended when diltiazem is used with atazanavir. Additionally, atazanavir can prolong the PR interval, especially with high serum concentrations. Greater lengthening of the PR interval with the combined use of diltiazem and atazanavir as compared to either alone has been documented. (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with cobicistat is necessary. Diltiazem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Atenolol: (Moderate) The combination of diltiazem and a beta-blocker, like atenolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Atenolol; Chlorthalidone: (Moderate) The combination of diltiazem and a beta-blocker, like atenolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Atorvastatin: (Major) According to the manufacturer of diltiazem, clinicians should consider use of a non-CYP3A4-metabolized statin (e.g., pitavastatin, pravastatin, rosuvastatin) in combination with diltiazem. Coadministration of atorvastatin 40 mg with diltiazem 240 mg was associated with a higher plasma concentration of atorvastatin. Increased concentrations of atorvastatin are associated with an increased risk of myopathy and rhabdomyolysis. Diltiazem is a CYP3A4 inhibitor; coadministration with atorvastatin (CYP3A4 substrate) may result in increased concentrations of atorvastatin.
    Atorvastatin; Ezetimibe: (Major) According to the manufacturer of diltiazem, clinicians should consider use of a non-CYP3A4-metabolized statin (e.g., pitavastatin, pravastatin, rosuvastatin) in combination with diltiazem. Coadministration of atorvastatin 40 mg with diltiazem 240 mg was associated with a higher plasma concentration of atorvastatin. Increased concentrations of atorvastatin are associated with an increased risk of myopathy and rhabdomyolysis. Diltiazem is a CYP3A4 inhibitor; coadministration with atorvastatin (CYP3A4 substrate) may result in increased concentrations of atorvastatin.
    Atracurium: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Avanafil: (Moderate) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Particular caution should be used when prescribing avanafil to patients receiving concomitant moderate CYP3A4 inhibitors such as diltiazem. For example, erythromycin increased avanafil Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours. Therefore, during coadministration, the maximum recommended adult dose of avanafil is 50 mg, not to exceed once every 24 hours.
    Baclofen: (Moderate) 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: (Major) Diltiazem is a CYP3A4 substrate. Coadministration of diltiazem with known CYP3A4 inducers, such as barbiturates, may significantly decrease the bioavailability of diltiazem. When possible, avoid coadministration of these drugs and consider alternative therapy. When an alternative therapy is not possible, patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and diltiazem together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of diltiazem, a CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Bendroflumethiazide; Nadolol: (Moderate) The combination of diltiazem and a beta-blocker, like nadolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Benzonatate: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Benzphetamine: (Major) 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
    Bepridil: (Moderate) Calcium-channel blockers, including bepridil, can have additive hypotensive effects with other antihypertensive agents.
    Betaxolol: (Moderate) The combination of diltiazem and a beta-blocker, like betaxolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Bisoprolol: (Moderate) The combination of diltiazem and a beta-blocker, like bisoprolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) The combination of diltiazem and a beta-blocker, like bisoprolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Bortezomib: (Moderate) 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: (Moderate) 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.
    Bosutinib: (Major) Avoid concomitant use of bosutinib and diltiazem as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
    Bretylium: (Major) Concomitant use of bretylium with other antiarrhythmis, such as diltiazem, can have additive, antagonistic, or synergistic electrophysiologic, pharmacodynamic, or toxic effects, including hypotension. Combined antiarrhythmic therapy may necessitate a reduction in antiarrhythmic drug dosages, to decrease the potential for toxicity.
    Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to 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. Diltiazem is a moderate inhibitor of CYP3A4. If diltiazem is used in combination with brexpiprazole and a moderate to strong CYP2D6 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions. A reduction of the brexpiprazole dose to 25% of the usual dose is also recommended in patients who are poor metabolizers of CYP2D6 and are receiving a moderate CYP3A4 inhibitor.
    Brigatinib: (Moderate) Monitor for reduced response to diltiazem if coadministration of brigatinib is necessary. Dosages of diltiazem may need to be adjusted while the patient is receiving brigatinib. Brigatinib is a CYP3A4 inducer, although the strength of induction is unknown. Diltiazem is a CYP3A4 substrate. Coadministration with a strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable levels.
    Brimonidine; Timolol: (Moderate) The combination of diltiazem and a beta-blocker, like timolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of diltiazem. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; diltiazem is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Brompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Budesonide: (Minor) Diltiazem may increase plasma concentrations of oral budesonide due to inhibition of the CYP3A4 isoenzymet, and can enhance the cortisol suppression associated with budesonide administered via inhalation.
    Budesonide; Formoterol: (Minor) Diltiazem may increase plasma concentrations of oral budesonide due to inhibition of the CYP3A4 isoenzymet, and can enhance the cortisol suppression associated with budesonide administered via inhalation.
    Bupivacaine Liposomal: (Moderate) Diltiazem may inhibit the CYP3A4-mediated metabolism of bupivacaine. Use caution when administering these drugs concomitantly.
    Bupivacaine: (Moderate) Diltiazem may inhibit the CYP3A4-mediated metabolism of bupivacaine. Use caution when administering these drugs concomitantly.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and diltiazem may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; diltiazem inhibits CYP3A4. (Moderate) Diltiazem may inhibit the CYP3A4-mediated metabolism of bupivacaine. Use caution when administering these drugs concomitantly.
    Buprenorphine: (Moderate) Diltiazem is an inhibitor of the CYP3A4 isoenzyme. Co-administration with diltiazem may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as buprenorphine.
    Buprenorphine; Naloxone: (Moderate) Diltiazem is an inhibitor of the CYP3A4 isoenzyme. Co-administration with diltiazem may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as buprenorphine.
    Buspirone: (Moderate) Coadministration of buspirone with diltiazem substantially increases the plasma concentration of buspirone. During coadministration with diltiazem, close monitoring is suggested, with adjustment of buspirone dosage if needed.
    Cabergoline: (Major) Diltiazem is an inhibitor of the CYP3A4 isoenzyme. Co-administration with diltiazem may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as cabergoline.
    Caffeine; Ergotamine: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and diltiazem together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of diltiazem, a CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Cannabidiol: (Moderate) Consider a dose reduction of cannabidiol if coadministered with diltiazem. Coadministration may increase cannabidiol plasma concentrations increasing the risk of adverse reactions. Cannabidiol is metabolized by CYP3A4; diltiazem is a moderate inhibitor of CYP3A4.
    Carbamazepine: (Major) Avoid coadministration of diltiazem and carbamazepine due to decreased plasma concentrations of diltiazem. Additionally, concomitant administration of diltiazem and carbamazepine has been reported to result in a 40% to 72% increase in carbamazepine plasma concentration resulting in toxicity in some cases. Monitor patients receiving these drugs concurrently for altered clinical response to therapy. Diltiazem is a CYP3A4 substrate and moderate inhibitor; carbamazepine is a CYP3A4 substrate and strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Carbinoxamine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbinoxamine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Cariprazine: (Moderate) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Diltiazem 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: (Moderate) The combination of diltiazem and a beta-blocker, like carteolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Carvedilol: (Moderate) The combination of diltiazem and a beta-blocker, like carvedilol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Celecoxib: (Moderate) 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: (Major) Avoid coadministration of ceritinib with diltiazem due to increased diltiazem exposure and the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary for bradycardia. If coadministration is unavoidable, monitor heart rate and blood pressure regularly. Ceritinib is a CYP3A4 inhibitor and diltiazem is metabolized by CYP3A4.
    Cetirizine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Cevimeline: (Moderate) Cevimeline is metabolized by cytochrome P450 3A4 and CYP2D6. In theory, concurrent administration of inhibitors of CYP3A4, such as diltiazem, may lead to increased cevimeline plasma concentrations.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlordiazepoxide: (Moderate) Diltiazem could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide.
    Chlordiazepoxide; Clidinium: (Moderate) Diltiazem could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with diltiazem may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Diltiazem is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with diltiazem may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Diltiazem is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with diltiazem may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Diltiazem is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlorpheniramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlorthalidone; Clonidine: (Moderate) Monitor heart rate in patients receiving concomitant clonidine and agents known to affect sinus node function or AV nodal conduction (e.g., diltiazem). Complete AV block resulting in a nodal rhythm and sinus bradycardia resulting in hospitalization and pacemaker insertion have been reported during combination therapy of clonidine with diltiazem or verapamil.
    Cilostazol: (Major) Diltiazem can potentially inhibit the CYP3A4 metabolism of cilostazol. The coadministration of diltiazem and cilostazol increases the AUC of cilostazol by approximately 40%, presumably by inhibition of CYP3A4 metabolism. When diltiazem or other significant CYP3A4 inhibitors are coadministered with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
    Cimetidine: (Moderate) Cimetidine can increase the plasma levels of diltiazem, possibly via inhibition of cytochrome P-450 metabolism. Concurrent cimetidine and diltiazem therapy may require a reduction in diltiazem dosage in some patients; monitor clinical response.
    Cinacalcet: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include diltiazem. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Ciprofloxacin: (Moderate) Caution and monitoring is warranted with the use of ciprofloxacin and diltiazem. Monitor for adverse events such as a decrease in blood pressure or heart rate. Coadministration of ciprofloxacin, a CYP3A4 inhibitor, with diltiazem, a CYP3A4 substrate, may result in elevated diltiazem serum concentrations.
    Cisapride: (Severe) Caution should be taken when cisapride (CYP3A4 substrate) is prescribed with diltiazem (CYP3A4 inhibitor); the manufacturer of cisapride considers concurrent use contraindicated. A possible drug interaction occurred in a 45-year-old woman taking cisapride with diltiazem who had near syncopal effects and QT-interval prolongation. After discontinuing cisapride, the QT interval returned to normal without recurrence of symptoms. Prolongation of QT interval, torsades de pointes, and sudden cardiac death have been reported after concomitant administration of cisapride (a CYP3A4 substrate) with other CYP3A4 inhibitors.
    Cisatracurium: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Citalopram: (Moderate) During concurrent use of citalopram and diltiazem, clinicians should monitor patients for a potential increase in side effects or toxicity. In theory, diltiazem may inhibit the metabolism of citalopram through inhibition of CYP3A4. It should be noted that because citalopram is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease citalopram clearance.
    Clarithromycin: (Major) 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 crossover 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.
    Clindamycin: (Moderate) Concomitant use of clindamycin and diltiazem may decrease clindamycin clearance and increase the risk of adverse reactions. Clindamycin is a CYP3A4 substrate; diltiazem is a moderate inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Clonazepam: (Moderate) CYP3A4 inhibitors, such as diltiazem, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity.
    Clonidine: (Moderate) Monitor heart rate in patients receiving concomitant clonidine and agents known to affect sinus node function or AV nodal conduction (e.g., diltiazem). Complete AV block resulting in a nodal rhythm and sinus bradycardia resulting in hospitalization and pacemaker insertion have been reported during combination therapy of clonidine with diltiazem or verapamil.
    Clorazepate: (Moderate) Diltiazem is a CYP3A4 inhibitor and may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity.
    Clozapine: (Moderate) Caution is advisable during concurrent use of diltiazem and clozapine. Diltiazem is an inhibitor of CYP3A4, one 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, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with cobicistat is necessary. Diltiazem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with cobicistat is necessary. Diltiazem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with cobicistat is necessary. Diltiazem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with diltiazem therapy due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate; diltiazem is a moderate inhibitor of CYP3A.
    Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.
    Cod Liver Oil: (Moderate) 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. (Moderate) 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: (Moderate) Concomitant use of codeine with diltiazem may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Diltiazem is a moderate inhibitor of CYP3A4.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with diltiazem may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Diltiazem is a moderate inhibitor of CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with diltiazem may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with diltiazem may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Diltiazem is a moderate inhibitor of CYP3A4.
    Co-Enzyme Q10, Ubiquinone: (Moderate) 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: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and diltiazem in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Diltiazem can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken diltiazem in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day.
    Colesevelam: (Moderate) Colesevelam may decrease the absorption of diltiazem. To minimize potential for interactions, consider administering diltiazem at least 1 hour before or at least 4 hours after colesevelam.
    Conivaptan: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and diltiazem, a CYP3A4 substrate, due to the potential for elevated concentrations of diltiazem. According to the manufacturer of conivaptan, 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 also 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.
    Conjugated Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as diltiazem may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as diltiazem may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as diltiazem may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Crizotinib: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as diltiazem, to the extent possible due to the risk of additive bradycardia; increased exposure to both drugs may also occur. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly, and watch for an increase in crizotinib-related adverse reactions. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs. Crizotinib and diltiazem are both CYP3A substrates and moderate inhibitors.
    Cyclosporine: (Moderate) Diltiazem inhibits CYP3A4 metabolism and thereby increases cyclosporine serum concentrations. Cyclosporine dosage reduction (20 to 50%) may be required when diltiazem therapy is initiated to prevent cyclosporine toxicity.
    Danazol: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Dantrolene: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Dapagliflozin; Saxagliptin: (Minor) Saxagliptin did not meaningfully alter the pharmacokinetics of diltiazem. However, coadministration increased the maximum serum saxagliptin concentration by 63% and the systemic exposure by 2.1-fold. As expected, the maximum serum concentration of the saxagliptin active metabolite was decreased by 44% and the systemic exposure was decreased by 36%. Saxagliptin dose adjustment is not advised when coadministered with diltiazem.
    Darifenacin: (Moderate) Darifenacin is a substrate for CYP3A4 and, theoretically, plasma concentrations could be increased via CYP3A4 inhibition by diltiazem, a moderate inhibitor.
    Darunavir: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Complex interactions can be expected with coadministered with diltiazem or verapamil, as both are substrates and inhibitors of CYP3A4.
    Darunavir; Cobicistat: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Complex interactions can be expected with coadministered with diltiazem or verapamil, as both are substrates and inhibitors of CYP3A4. (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with cobicistat is necessary. Diltiazem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Complex interactions can be expected with coadministered with diltiazem or verapamil, as both are substrates and inhibitors of CYP3A4. (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with cobicistat is necessary. Diltiazem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir is expected to decreases the hepatic CYP metabolism of diltiazem, resulting in increased diltiazem concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased diltiazem may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with diltiazem. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; diltiazem is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as diltiazem, should be expected with concurrent use of delavirdine.
    Desloratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Dexmedetomidine: (Moderate) Concomitant administration of dexmedetomidine and calcium-channel blockers could lead to additive hypotension and bradycardia; use together with caution. Dexmedetomidine can produce bradycardia or AV block and should be used cautiously in patients who are receiving antihypertensive drugs that may lower the heart rate such as calcium-channel blockers.
    Dexmethylphenidate: (Moderate) Dexmethylphenidate can reduce the hypotensive effect of antihypertensive agents, including calcium-channel blockers. Periodic evaluation of blood pressure is advisable during concurrent use of dexmethylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of dexmethylphenidate.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Dextromethorphan; Quinidine: (Major) Diltiazem significantly decreases the clearance and increases the half-life of quinidine. Quinidine does not alter the kinetics of diltiazem. Concurrent use of diltiazem and quinidine in some patients may cause additive hypotension. Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction. Medications that possess negative inotropic effects and/or slow AV conduction, such as quinidine, should be administered with caution to patients receiving concomitant therapy with diltiazem due to the risk of additive effects. Diltiazem may increase serum quinidine concentrations (AUC increases by 51%) by reducing the oral clearance of quinidine by 33%. During diltiazem coadministration, monitor quinidine serum concentrations and therapeutic response; adjust quinidine dosage if needed.
    Diazepam: (Moderate) Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4. As a result, diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes, such as diltiazem.
    Diazoxide: (Moderate) 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: (Moderate) 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: (Moderate) 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.
    Dienogest; Estradiol valerate: (Minor) As diltiazem inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Diethylpropion: (Major) 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: (Moderate) 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: (Major) Coadministration of digoxin and diltiazem increases the serum concentration of digoxin by 20%. It is believed that diltiazem decreases renal and nonrenal clearance of digoxin. Measure serum digoxin concentrations before initiating diltiazem. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Despite the potential for interactions, digoxin sometimes is intentionally used in combination with diltiazem to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with diltiazem may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of diltiazem could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Diltiazem is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Dihydroergotamine: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine and diltiazem together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of diltiazem, a CYP3A4 inhibitor, and dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Diphenhydramine; Ibuprofen: (Moderate) 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; Naproxen: (Moderate) 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: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Disopyramide: (Major) Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction such as disopyramide. In addition, diltiazem can theoretically inhibit the CYP3A4 metabolism of disopyramide.
    Dofetilide: (Major) Diltiazem should be used with caution with dofetilide since it may increase dofetilide plasma concentrations via inhibition of CYP3A4 metabolism. This interaction may increase the potential for dofetilide-induced proarrhythmias.
    Dolasetron: (Major) Dolasetron has been associated with a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Therefore, drugs known to prolong the PR interval, such as diltiazem, should be avoided in patients taking dolasetron.
    Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering diltiazem 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. Diltiazem is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Donepezil: (Minor) Diltiazem may inhibit the metabolism of donepezil by inhibiting CYP3A4. The clinical effect of this interaction on the response to donepezil has not been determined.
    Donepezil; Memantine: (Minor) Diltiazem may inhibit the metabolism of donepezil by inhibiting CYP3A4. The clinical effect of this interaction on the response to donepezil has not been determined.
    Dorzolamide; Timolol: (Moderate) The combination of diltiazem and a beta-blocker, like timolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Doxacurium: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like diltiazem, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with doxercalciferol.
    Doxorubicin: (Major) Avoid coadministration of diltiazem and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. Diltiazem is a moderate CYP3A4 inhibitor; doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin.
    Dronabinol: (Major) Use caution if coadministration of dronabinol with diltiazem 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; diltiazem is a moderate inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Major) If coadministered with dronedarone, initiate diltiazem at a low dose and increase only after ECG verification of good tolerability. Both diltiazem and dronedarone are substrates and moderate CYP3A4 inhibitors; increased exposure to both drugs may occur. Additionally, the conduction effects of dronedarone may be potentiated by concurrent use of calcium channel blockers with depressant effects on the sinus and AV nodes.
    Drospirenone; Estradiol: (Minor) As diltiazem inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Drospirenone; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Duloxetine: (Moderate) 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: (Moderate) Dutasteride is metabolized by CYP3A4 enzyme and the clearance of dutasteride may be reduced when co-administered with the CYP3A4 inhibitor diltiazem.
    Dutasteride; Tamsulosin: (Moderate) Dutasteride is metabolized by CYP3A4 enzyme and the clearance of dutasteride may be reduced when co-administered with the CYP3A4 inhibitor diltiazem. (Moderate) 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.
    Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib and diltiazem during coadministration. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; diltiazem is also a substrate and moderate inhibitor of CYP3A.
    Efavirenz: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. 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 should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. 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 should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. 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 should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Elagolix: (Moderate) Use caution and careful monitoring when coadministering elagolix with diltiazem; diltiazem exposure and effect may be decreased. Dose adjustments should be made for diltiazem based on clinical response. Elagolix is a weak to moderate CYP3A4 inducer. Diltiazem is a CYP3A4 substrate.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with diltiazem may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Diltiazem is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with diltiazem. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and diltiazem is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
    Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of diltiazem and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both diltiazem and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Diltiazem is a moderate CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors, such as diltiazem, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
    Empagliflozin: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Moderate) Close clinical monitoring is advised when administering diltiazem 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. Diltiazem 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: (Moderate) Close clinical monitoring is advised when administering diltiazem 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. Diltiazem is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Encainide: (Major) Diltiazem has been shown to increase encainide AUC and half-life. These findings have been observed when both drugs were given orally. While the changes in encainide pharmacokinetics were statistically significant, no ECG or pharmacodynamic changes were seen. This may be explained by the fact that the kinetics of encainide's active metabolites did not change during diltiazem administration.
    Encorafenib: (Major) Avoid coadministration of encorafenib and diltiazem due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of diltiazem. If diltiazem is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of diltiazem. Encorafenib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration of diltiazem with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Enflurane: (Major) 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.
    Enzalutamide: (Major) Avoid coadministration of diltiazem and enzalutamide due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable.
    Ephedrine: (Major) 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: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, 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. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Diltiazem is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Epoprostenol: (Moderate) 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: (Major) Diltiazem is an inhibitor of the CYP3A4 isoenzyme. Coadministration with diltiazem may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as ergoloid mesylates.
    Ergonovine: (Major) 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: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and diltiazem together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of diltiazem, a CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Erythromycin: (Major) 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 verapamil) 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: (Major) 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 verapamil) 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: (Minor) Escitalopram is metabolized by CYP3A4 and CYP2C19. Diltiazem can inhibit the metabolism of CYP 450 isoenzymes, including those that are responsible for the metabolism of escitalopram. Although clinical studies have not been done to determine the clinical significance of such an interaction, the potential for increased adverse effects and toxicity associated with elevated plasma levels of escitalopram theoretically exists.
    Esmolol: (Moderate) The combination of diltiazem and a beta-blocker, like esmolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Esomeprazole; Naproxen: (Moderate) 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: (Moderate) Diltiazem is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
    Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as diltiazem may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as diltiazem may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) As diltiazem inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol: (Minor) As diltiazem inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Levonorgestrel: (Minor) As diltiazem inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norethindrone: (Minor) As diltiazem inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norgestimate: (Minor) As diltiazem inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as diltiazem may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Eszopiclone: (Moderate) Although data are not available, CYP3A4 inhibitors, such as diltiazem, may decrease systemic clearance of eszopiclone leading to prolonged effects. If eszopiclone is to be administered concurrently with significant CYP3A4 inhibitors, a decreased dose of eszopiclone may be warranted. Subsequent dosage adjustments should be based on clinical response.
    Ethanol: (Major) Patients must avoid consumption of alcohol with some dosage forms of diltiazem; also, advise patients to limit alcohol ingestion with diltiazem in general since there may be additive effects on blood pressure that may increase the risk for orthostatic hypotension, dizziness or syncope. Alcohol increases the rate at which some controlled and extended release formulas of diltiazem (such as Cardizem CD) release diltiazem in vitro. This effect may lead to more rapid absorption and an increase in the systemic exposure of diltiazem, and associated dose-related adverse reactions. (Major) Patients must avoid consumption of alcohol with some dosage forms of diltiazem; also, advise patients to limit alcohol ingestion with diltiazem in general since there may be additive effects on blood pressure that may increase the risk for orthostatic hypotension, dizziness, or syncope. Alcohol increases the rate at which some controlled and extended release formulas of diltiazem (such as Cardizem CD) release diltiazem in vitro. This effect may lead to more rapid absorption and an increase in the systemic exposure of diltiazem, and associated dose-related adverse reactions.
    Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Desogestrel: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as diltiazem may increase the serum concentration of etonogestrel. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norelgestromin: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norgestimate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norgestrel: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethosuximide: (Moderate) Diltiazem is an inhibitor of the CYP3A4 isoenzyme. Co-administration with diltiazem may lead to an increase in serum levels of drugs that are CYP3A4 substrates including ethosuximide.
    Etodolac: (Moderate) 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: (Major) 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.
    Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as diltiazem may increase the serum concentration of etonogestrel.
    Etoposide, VP-16: (Moderate) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with diltiazem. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations. Diltiazem is a CYP3A4 inhibitor; etoposide, VP-16 is a substrate CYP3A4.
    Etravirine: (Moderate) Caution is warranted if diltiazem and etravirine are coadministered as diltiazem exposure may be decreased and etravirine exposure may be increased. Etravirine is a CYP3A4 inducer/substrate and diltiazem is a CYP3A4 substrate/inhibitor.
    Everolimus: (Major) A dose adjustment of everolimus is necessary when prescribed with diltiazem due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If diltiazem is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If diltiazem is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    Ezetimibe; Simvastatin: (Major) Do not exceed a simvastatin dose of 10 mg/day and a diltiazem dose of 240 mg/day if coadministered due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on diltiazem, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of diltiazem and simvastatin against the potential risks. Diltiazem increases the simvastatin exposure by approximately 5-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism by diltiazem.
    Famotidine; Ibuprofen: (Moderate) 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: (Moderate) 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: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. If diltiazem is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a CYP3A4 inhibitor like diltiazem can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If diltiazem is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Fesoterodine: (Moderate) Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4. In theory, the CYP3A4 inhibitory effects of diltiazem may result in an increase in plasma concentrations of 5-hydroxymethyltolterodine. The need for fesoterodine doses greater than 4 mg/day should be carefully evaluated prior to increasing the dose during concurrent use of mild to moderate 3A4 inhibitors.
    Fexofenadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Fingolimod: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as heart-rate slowing calcium channel blockers like diltiazem. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) 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. (Moderate) 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.
    Flecainide: (Major) Concomitant administration of diltiazem and flecainide has the potential to cause additive decreases in AV conduction and/or negative inotropic effects. There is insufficient experience with flecainide use with diltiazem to recommend combined therapy.
    Flibanserin: (Severe) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as diltiazem, 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: (Moderate) Fluconazole may decrease the clearance of calcium-channel blockers, including diltiazem, via inhibition of CYP3A4 metabolism.
    Fluoxetine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers via inhibition of CYP3A4 metabolism.
    Fluoxetine; Olanzapine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers via inhibition of CYP3A4 metabolism. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Flurazepam: (Moderate) Diltiazem could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, such as flurazepam. Use these drugs together cautiously, and monitor the patient for benzodiazepine-related side effects.
    Flurbiprofen: (Moderate) 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: (Moderate) Fluvoxamine may decrease the clearance of calcium-channel blockers, including diltiazem, via inhibition of CYP3A4 metabolism. Bradycardia has been reported when fluvoxamine has been added to a stable diltiazem regimen.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with diltiazem. Diltiazem 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 diltiazem, 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: (Moderate) Fosamprenavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4. Although drug interaction studies have not been conducted, the serum concentration of diltiazem may be increased with concomitant administration of fosamprenavir.
    Fosphenytoin: (Major) Avoid coadministration of diltiazem and fosphenytoin due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and phenytoin, the active metabolite of fosphenytoin, is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable.
    Fospropofol: (Major) 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.
    General anesthetics: (Major) 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.
    Ginger, Zingiber officinale: (Minor) In vitro studies have demonstrated the positive inotropic effects of certain gingerol constituents of ginger; but it is unclear if whole ginger root exhibits these effects clinically in humans. It is theoretically possible that excessive doses of ginger could affect the action of inotropes; however, no clinical data are available.
    Ginkgo, Ginkgo biloba: (Moderate) 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: (Moderate) 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: (Moderate) Current data suggest that grapefruit juice has a limited effect on diltiazem bioavailability. The mechanism is most likely due to inhibition of CYP3A4 isoenzymes in the gut by inhibitory compounds within grapefruit juice, resulting in reduced first-pass drug metabolism. It is generally recommended to avoid grapefruit juice during calcium-channel blocker therapy.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Guanfacine: (Major) Diltiazem may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon diltiazem discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and diltiazem is a moderate CYP3A4 inhibitor.
    Halofantrine: (Moderate) Drugs which significantly inhibit cytochrome CYP3A4, such as diltiazem, may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity. If concurrent use of halofantrine and a CYP3A4 inhibitor is warranted, it would be prudent to use caution and monitor the ECG periodically.
    Haloperidol: (Moderate) In general, antipsychotics like haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension. Diltiazem and verapamil are substrates and inhibitors of CYP3A4. 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 CYP2D6 or CYP3A4 may increase the risk of adverse effects, including QT prolongation.
    Halothane: (Major) 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: (Moderate) 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: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) 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: (Moderate) The combination of diltiazem and a beta-blocker, like metoprolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) The combination of diltiazem and a beta-blocker, like propranolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block. In addition, diltiazem has been shown to inhibit the metabolism of propranolol and increase bioavailability by 50%.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) 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: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Hydroxyprogesterone: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes, like dilitiazem, would have a similar effect.
    Ibrutinib: (Major) If coadministered with diltiazem, reduce the ibrutinib dose to 280 mg/day PO for the treatment of B-cell malignancies. Resume ibrutinib at the previous dose if diltiazem is discontinued. Initiate ibrutinib at the recommended dose of 420 mg/day PO for the treatment of chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interruption of ibrutinib therapy or a dose reduction may be necessary in patients who develop severe toxicity. Ibrutinib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ibuprofen: (Moderate) 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: (Moderate) Concomitant use of oxycodone with diltiazem may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and diltiazem is a CYP3A4 inhibitor. (Moderate) 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: (Moderate) 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. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with diltiazem, a CYP3A substrate, as diltiazem toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with diltiazem is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Diltiazem is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Iloperidone: (Moderate) 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: (Moderate) 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: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including diltiazem.
    Imipramine: (Moderate) Diltiazem inhibits the CYP3A4 metabolism of imipramine and decreases oral clearance by 35%. Imipramine serum concentrations are suggested to monitor imipramine therapy when adding diltiazem therapy or changing diltiazem dosage.
    Indinavir: (Moderate) Indinavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4. Although drug interaction studies have not been conducted, the serum concentration of diltiazem may be increased with concomitant administration of indinavir.
    Indomethacin: (Moderate) 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.
    Intravenous Lipid Emulsions: (Moderate) 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.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with diltiazem may result in increased serum concentrations of both drugs. Diltiazem is a substrate and inhibitor of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: (Moderate) 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: (Major) 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: (Major) Avoid coadministration of diltiazem and rifampin due to decreased plasma concentrations of diltiazem. Coadministration with rifampin lowered diltiazem plasma concentrations to undetectable. Diltiazem is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of diltiazem and rifampin due to decreased plasma concentrations of diltiazem. Coadministration with rifampin lowered diltiazem plasma concentrations to undetectable. Diltiazem is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer.
    Isoproterenol: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase diltiazem serum concentrations via inhibition of CYP3A4 with the potential for diltiazem 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: (Major) Avoid coadministration of ivabradine and diltiazem. Both ivabradine and diltiazem may cause bradycardia. In addition, ivabradine is primarily metabolized by CYP3A4; diltiazem inhibits CYP3A4. Coadministration may increase the plasma concentrations of ivabradine further increasing the risk for bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Major) If diltiazem and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with diltiazem due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with strong CYP3A4 inhibitors such as diltiazem should be avoided. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider an ixabepilone dose reduction. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose.
    Ketamine: (Major) 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: (Moderate) Ketoconazole may increase diltiazem serum concentrations via inhibition of CYP3A4 with the potential for diltiazem toxicity. Exercise caution when co-administering systemic azole antifungals and calcium-channel blockers.
    Ketoprofen: (Moderate) 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: (Moderate) 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: (Moderate) The combination of diltiazem and a beta-blocker, like labetalol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as calcium-channel blockers, because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
    Lanreotide: (Moderate) Concomitant administration of bradycardia-inducing drugs (e.g., calcium-channel blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Adjust the calcium-channel blocker dose if necessary.
    Lansoprazole; Naproxen: (Moderate) 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: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with strong CYP3A4 inhibitors, such as diltiazem, should generally be avoided. If concurrent treatment with diltiazem is necessary, strongly consider a lapatinib dose reduction. If diltiazem is discontinued, allow 7 days to elapse before increasing the lapatinib dose.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of diltiazem may occur during concurrent administration with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. If these drugs are given together, closely monitor for diltiazem-related adverse events (e.g., bradycardia, hypotension, hepatotoxicity). Diltiazem is metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
    Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Levomilnacipran: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of diltiazem may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and diltiazem may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; diltiazem inhibits CYP3A4.
    Lisdexamfetamine: (Major) 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: (Major) 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.
    Lofexidine: (Moderate) Because both lofexidine and diltiazem can cause hypotension and bradycardia, concurrent use should be avoided if possible. Patients being given lofexidine in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis, bradycardia, and associated symptoms. If clinically significant or symptomatic hypotension and/or bradycardia occur, the next dose of lofexidine should be reduced in amount, delayed, or skipped.
    Lomitapide: (Severe) Concomitant use of diltiazem and lomitapide is contraindicated. If treatment with diltiazem is unavoidable, lomitapide should be stopped during the course of treatment. Diltiazem is a moderate CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor. Although concomitant use of moderate CYP3A4 inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use.
    Loperamide: (Moderate) 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) if coadministered with diltiazem.The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with diltiazem, a CYP3A4 inhibitor.
    Loperamide; Simethicone: (Moderate) 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) if coadministered with diltiazem.The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with diltiazem, a CYP3A4 inhibitor.
    Lopinavir; Ritonavir: (Major) Ritonavir is expected to decreases the hepatic CYP metabolism of diltiazem, resulting in increased diltiazem concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased diltiazem may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration. (Moderate) Lopinavir may decrease the clearance of diltiazem via inhibition of CYP3A4 metabolism. Caution is warranted and clinical monitoring of the patient is recommended.
    Loratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Lorlatinib: (Major) Avoid coadministration of diltiazem and lorlatinib if possible due to decreased plasma concentrations of diltiazem; if unavoidable, monitor blood pressure and heart rate and adjust the diltiazem dose based on clinical response. Diltiazem is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased diltiazem exposure by 69% and decreased exposure to desacetyldiltiazem by 75%.
    Lovastatin: (Major) Coadministration of diltiazem and lovastatin increases the risk for myopathy/rhabdomyolysis particularly with higher doses of lovastatin. In adult patients taking diltiazem, the initial lovastatin dose should not exceed 10 mg/day PO, and the total lovastatin dose should not exceed 20 mg/day PO. The benefits of the use of lovastatin in patients taking diltiazem should be carefully weighed against the risks of this combination.
    Lovastatin; Niacin: (Major) Coadministration of diltiazem and lovastatin increases the risk for myopathy/rhabdomyolysis particularly with higher doses of lovastatin. In adult patients taking diltiazem, the initial lovastatin dose should not exceed 10 mg/day PO, and the total lovastatin dose should not exceed 20 mg/day PO. The benefits of the use of lovastatin in patients taking diltiazem should be carefully weighed against the risks of this combination. (Moderate) 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.
    Lumacaftor; Ivacaftor: (Major) Avoid concomitant use and consider alternative therapy when possible. Lumacaftor; ivacaftor may reduce the efficacy of diltiazem by decreasing its systemic exposure. Monitor cardiovascular effects (e.g., heart rate, chest pain, blood pressure) closely and adjust the diltiazem dosage as appropriate. Diltiazem is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer. Coadministration of diltiazem and a strong CYP3A inducer resulted in undetectable diltiazem plasma concentrations.
    Lumacaftor; Ivacaftor: (Major) If diltiazem and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Lurasidone: (Major) Diltiazem is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity. When a single dose of lurasidone 20 mg was co-administered with diltiazem 240 mg/day for 5 days, the lurasidone Cmax and AUC increased by 2.1-times and 2.2-times, respectively, compared to those seen after the administration of lurasidone alone. In addition, due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects antihypertensive agents. If coadministration 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.
    Maraviroc: (Moderate) Monitor for an increase in maraviroc adverse effects with concomitant use of diltiazem due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and diltiazem is a CYP3A4 inhibitor.
    Meclofenamate Sodium: (Moderate) 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: (Moderate) 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: (Moderate) Mefloquine is metabolized by CYP3A4. Diltiazem is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
    Melatonin: (Moderate) 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: (Moderate) 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.
    Mestranol; Norethindrone: (Minor) 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: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Diltiazem is an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Metformin; Saxagliptin: (Minor) Saxagliptin did not meaningfully alter the pharmacokinetics of diltiazem. However, coadministration increased the maximum serum saxagliptin concentration by 63% and the systemic exposure by 2.1-fold. As expected, the maximum serum concentration of the saxagliptin active metabolite was decreased by 44% and the systemic exposure was decreased by 36%. Saxagliptin dose adjustment is not advised when coadministered with diltiazem.
    Methadone: (Moderate) Concurrent administration with CYP3A4 inhibitors, such as diltiazem, may result in increased concentrations of methadone. Inhibition of methadone metabolism can lead to toxicity including CNS adverse effects and potential for QT prolongation and torsades de pointes when high doses of methadone are used (e.g., 200 mg/day PO in adult patients).
    Methamphetamine: (Major) 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.
    Methoxsalen: (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylergonovine: (Moderate) Be alert for symptoms of ergot toxicity if using methylergonovine and diltiazem together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of diltiazem, a CYP3A4 inhibitor, and methylergonovine, a CYP3A4 substrate, may result in increased ergot alkaloid levels.
    Methylphenidate: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents, including calcium-channel blockers. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Methylprednisolone: (Moderate) Diltiazem may decrease the metabolism of methylprednisolone via inhibition of the CYP3A4 isoenzyme, with the potential for increased corticosteroid effects. Oral coadministration of diltiazem and methylprednisolone has been shown to increase the AUC of methylprednisolone by about 2.6-fold and increase the half-life 1.9-fold.
    Methysergide: (Major) 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: (Moderate) The combination of diltiazem and a beta-blocker, like metoprolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Midazolam: (Moderate) Diltiazem may enhance and prolong the sedative effects of midazolam, and dosage reduction of midazolam and close monitoring is recommended during concurrent administration.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and diltiazem as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace diltiazem. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Midostaurin is a CYP3A4 substrate; diltiazem is a CYP3A4 inhibitor.
    Mifepristone: (Moderate) Mifepristone inhibits CYP3A4 and coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates, including many of the calcium-channel blockers. Drugs in which CYP3A is the primary route of metabolism should be used with caution if co-administered with mifepristone. The lowest possible dose and/or a decreased frequency of dosing must be used with therapeutic drug monitoring when possible. For calcium channel blockers, monitor blood pressure, heart rate, fluid retention and for shortness of breath as potential side effects. Avoiding calcium channel blockers by using other classes of antihypertensive agents that are not substrates for CYP3A4 may be appropriate in some patients requiring long-term administration of inhibitory drugs.
    Milnacipran: (Moderate) 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: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mitotane: (Major) Avoid coadministration of diltiazem and mitotane due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable.
    Mivacurium: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Moricizine: (Major) Coadministration of diltiazem and moricizine may increase both moricizine and diltiazem plasma concentrations.
    Nabumetone: (Moderate) 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: (Moderate) The combination of diltiazem and a beta-blocker, like nadolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with diltiazem. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4; diltiazem is a moderate CYP3A4 inhibitor.
    Naloxegol: (Major) Avoid concomitant administration of naloxegol and diltiazem due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration with diltiazem increased naloxegol exposure by approximately 3.4-fold.
    Nanoparticle Albumin-Bound Paclitaxel: (Minor) Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like diltiazem. These patients may require additional monitoring and information.
    Naproxen: (Moderate) 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: (Moderate) 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. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Naproxen; Sumatriptan: (Moderate) 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: (Moderate) The combination of diltiazem and a beta-blocker, like nebivolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Nebivolol; Valsartan: (Moderate) The combination of diltiazem and a beta-blocker, like nebivolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Nefazodone: (Moderate) Nefazodone is an inhibitor of CYP3A4 and may theoretically increase diltiazem serum concentrations with potential for toxicity.
    Nelfinavir: (Moderate) Nelfinavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4. Although drug interaction studies have not been conducted, the serum concentration of diltiazem may be increased with concomitant administration of nelfinavir.
    Neratinib: (Major) Avoid concomitant use of diltiazem with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Neuromuscular blockers: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Nevirapine: (Minor) 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: (Moderate) 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: (Major) Do not exceed a simvastatin dose of 10 mg/day and a diltiazem dose of 240 mg/day if coadministered due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on diltiazem, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of diltiazem and simvastatin against the potential risks. Diltiazem increases the simvastatin exposure by approximately 5-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism by diltiazem. (Moderate) 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.
    Nifedipine: (Moderate) Diltiazem has been reported to increase the plasma level and hypotensive effects of nifedipine via CYP3A4 inhibition.
    Nilotinib: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazeml with nilotinib is necessary; also monitor for nilotinib-related side effects. Nilotinib and diltiazeml are both substrates of and inhibitors of CYP3A4. Elevations of diltiazem plasma levels resulting in clinically significant interactions have been reported with other moderate CYP3A4 inhibitors. Increased nilotinib concentrations may increase the risk for treatment-related side effects.
    Nitrates: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olaparib: (Major) Avoid coadministration of olaparib with diltiazem and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir is expected to decreases the hepatic CYP metabolism of diltiazem, resulting in increased diltiazem concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased diltiazem may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration.
    Oritavancin: (Moderate) Diltiazem is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of diltiazem may be reduced if these drugs are administered concurrently.
    Oxaprozin: (Moderate) 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.
    Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Serum concentrations of oxybutynin may be increased if coadministered with inhibitors of CYP3A4 including diltiazem. The manufacturer recommends that caution when oxybutynin is co-administered with CYP3A4 inhibitors.
    Oxycodone: (Moderate) Concomitant use of oxycodone with diltiazem may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and diltiazem is a CYP3A4 inhibitor.
    Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by calcium-channel blockers. If these drugs are used together, closely monitor for changes in blood pressure.
    Paclitaxel: (Minor) Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as certain calcium-channel blockers, such as diltiazem. These patients should be monitored carefully. Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. Paclitaxel metabolism may be inhibited by diltiazem, a moderate CYP3A4 inhibitor. Combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses; monitor patients for symptoms and signs of toxicity, such as myelosuppression and peripheral neuropathy.
    Palbociclib: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with palbociclib is necessary. Diltiazem is a CYP3A4 substrate and palbociclib is a weak time-dependent CYP3A4 inhibitor.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving this combination who are susceptible to hypotension.
    Pancuronium: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Paricalcitol: (Moderate) Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as diltiazem. 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: (Major) 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.
    Penbutolol: (Moderate) The combination of diltiazem and a beta-blocker, like penbutolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Pentoxifylline: (Moderate) 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.
    Perindopril; Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate; coadministration of diltiazem 180 mg/day PO (CYP3A4 inhibitor) with amlodipine 5 mg/day PO in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. This effect might lead to hypotension or edema in some individuals. Caution should be used when diltiazem is coadministered with amlodipine; therapeutic response should be monitored.
    Phenelzine: (Moderate) 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.
    Phentermine; Topiramate: (Moderate) Coadministrator topiramate with diltiazem with caution. Concomitant administration of diltiazem (240 mg) with topiramate (150 mg/day) resulted in a 10% decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an 18% decrease in desacetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC of topiramate. Monitor for loss of diltiazem efficacy and or increased adverse events coming from the topiramate component of phentermine;topiramate.
    Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Phenylephrine; Promethazine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Phenytoin: (Major) Avoid coadministration of diltiazem and phenytoin due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable.
    Photosensitizing agents: (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Pimozide: (Severe) Concurrent use of pimozide and diltiazem should be avoided. Pimozide is metabolized primarily through CYP3A4, and diltiazem is a CYP3A4 inhibitor. Elevated pimozide concentrations occurring through inhibition of CYP3A4 can lead to QT prolongation, ventricular arrhythmias, and sudden death.
    Pindolol: (Moderate) The combination of diltiazem and a beta-blocker, like pindolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Piroxicam: (Moderate) 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: (Moderate) 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: (Moderate) 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.
    Prednisolone: (Moderate) Prednisolone is metabolized by CYP3A4 to inactive compounds. As diltiazem is both a substrate and an inhibitor of CYP3A4, monitor patients for corticosteroid-related side effects if prednisolone and diltiazem are taken.
    Prednisone: (Moderate) Prednisone is metabolized by the liver to the active metabolite prednisolone. Prednisolone is metabolized by CYP3A4 to inactive compounds. As diltiazem is both a substrate and an inhibitor of CYP3A4, monitor patients for corticosteroid-related side effects if prednisone and diltiazem are taken.
    Procainamide: (Moderate) 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: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Progesterone: (Minor) The metabolism of progesterone may be decreased by inhibitors of cytochrome P450 3A4 hepatic enzymes, such as diltiazem.
    Propafenone: (Major) Coadministration of propafenone with diltiazem has the potential to cause additive decreases in AV conduction and/or negative inotropic effects. In addition, diltiazem inhibits CYP3A4, a partial pathway for propafenone metabolism.
    Propofol: (Major) 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: (Moderate) The combination of diltiazem and a beta-blocker, like propranolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block. In addition, diltiazem has been shown to inhibit the metabolism of propranolol and increase bioavailability by 50%.
    Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Quazepam: (Moderate) CYP3A4 inhibitors, such as diltiazem, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity.
    Quetiapine: (Moderate) The cytochrome P450 3A4 (CYP3A4) isoenzyme is involved in the metabolism of quetiapine. Diltiazem may increase plasma concentrations of quetiapine through CYP3A4 inhibition. The manufacturer of quetiapine recommends a reduced dosage during concurrent administration of CYP3A4 inhibitors.
    Quinidine: (Major) Diltiazem significantly decreases the clearance and increases the half-life of quinidine. Quinidine does not alter the kinetics of diltiazem. Concurrent use of diltiazem and quinidine in some patients may cause additive hypotension. Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction. Medications that possess negative inotropic effects and/or slow AV conduction, such as quinidine, should be administered with caution to patients receiving concomitant therapy with diltiazem due to the risk of additive effects. Diltiazem may increase serum quinidine concentrations (AUC increases by 51%) by reducing the oral clearance of quinidine by 33%. During diltiazem coadministration, monitor quinidine serum concentrations and therapeutic response; adjust quinidine dosage if needed.
    Quinine: (Moderate) Monitor patients for increased side effects of quinine if administered with diltiazem; quinine concentrations could be increased with coadministration. Quinine is a substrate of CYP3A4, and diltiazem is a CYP3A4 inhibitor.
    Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as diltiazem, may lead to increases in the serum concentrations of ramelteon.
    Ranolazine: (Major) The dose of ranolazine, a CYP3A4 substrate, should be limited to 500 mg PO twice daily when coadministered with diltiazem, a moderate CYP3A inhibitor. Diltiazem (180 to 360 mg daily) causes dose-dependent increases in the average steady-state concentrations of ranolazine by about 2-fold.
    Rapacuronium: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Rasagiline: (Moderate) 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.
    Red Yeast Rice: (Severe) Since certain red yeast rice products contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. Diltiazem is a CYP3A4 inhibitor; CYP3A4 inhibitors have been shown to increase HMG-CoA reductase activity and potential for myopathy when coadministered with lovastatin. Because of these potential risks, red yeast rice is best avoided by patients taking diltiazem.
    Remifentanil: (Moderate) 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: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Diltiazem is an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Ribociclib: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with ribociclib is necessary. Diltiazem is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with ribociclib is necessary. Diltiazem is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Rifabutin: (Moderate) Diltiazem is a CYP3A4 substrate and inhibitor. Rifabutin is a CYP3A4 substrate and inducer. Coadministration of these drugs could lead to a complex interaction. Significant decreases in diltiazem concentrations could be seen, and significant increases in rifabutin concentrations could be seen. When possible, avoid coadministration of these drugs and consider alternative therapy. When an alternative therapy is not possible, patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure, as well as associated rifabutin side effects.
    Rifampin: (Major) Avoid coadministration of diltiazem and rifampin due to decreased plasma concentrations of diltiazem. Coadministration with rifampin lowered diltiazem plasma concentrations to undetectable. Diltiazem is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer.
    Rifapentine: (Moderate) Diltiazem is a CYP3A4 substrate. Coadministration of diltiazem with known CYP3A4 inducers, such as rifapentine, may significantly decrease the bioavailability of diltiazem. When possible, avoid coadministration of these drugs and consider alternative therapy. When an alternative therapy is not possible, patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure, as well as associated rifabutin side effects.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering diltiazem 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. Diltiazem is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Risperidone: (Moderate) Risperidone has been associated with orthostatic hypotension and may enhance the hypotensive effects of antihypertensive agents. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medications. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Ritonavir: (Major) Ritonavir is expected to decreases the hepatic CYP metabolism of diltiazem, resulting in increased diltiazem concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased diltiazem may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration.
    Rocuronium: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Rofecoxib: (Moderate) 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.
    Rucaparib: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with rucaparib is necessary. Diltiazem is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as diltiazem, 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: (Moderate) Saquinavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4. Although drug interaction studies have not been conducted, the serum concentration of diltiazem may be increased with concomitant administration of saquinavir.
    Saxagliptin: (Minor) Saxagliptin did not meaningfully alter the pharmacokinetics of diltiazem. However, coadministration increased the maximum serum saxagliptin concentration by 63% and the systemic exposure by 2.1-fold. As expected, the maximum serum concentration of the saxagliptin active metabolite was decreased by 44% and the systemic exposure was decreased by 36%. Saxagliptin dose adjustment is not advised when coadministered with diltiazem.
    Selegiline: (Moderate) 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.
    Sevoflurane: (Major) 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.
    Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with diltiazem is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    Silodosin: (Moderate) Monitor for silodosin-related adverse effects if coadministered with diltiazem; silodosin exposure may be increased. In addition the incidence of dizziness and orthostatic hypotension were increased in patients also receiving antihypertensive medications in clinical trials. Diltiazem is a moderate CYP3A4 inhibitor; silodosin is a CYP3A4 substrate. Although the effect of moderate CYP3A4 inhibitors on silodosin exposure has not been studied, coadministration of a strong inhibitor increased the silodosin AUC by 2.9-fold to 3.2-fold.
    Simvastatin: (Major) Do not exceed a simvastatin dose of 10 mg/day and a diltiazem dose of 240 mg/day if coadministered due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on diltiazem, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of diltiazem and simvastatin against the potential risks. Diltiazem increases the simvastatin exposure by approximately 5-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism by diltiazem.
    Simvastatin; Sitagliptin: (Major) Do not exceed a simvastatin dose of 10 mg/day and a diltiazem dose of 240 mg/day if coadministered due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on diltiazem, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of diltiazem and simvastatin against the potential risks. Diltiazem increases the simvastatin exposure by approximately 5-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism by diltiazem.
    Sincalide: (Moderate) 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: (Moderate) The simultaneous administration of sirolimus and diltiazem may significantly increase the bioavailability of sirolimus. This may be due to inhibition of sirolimus metabolism through the CYP3A pathway. Sirolimus blood trough concentrations should be monitored and dose adjustments may be necessary.
    Solifenacin: (Moderate) Use caution and monitor for an increase in solifenacin-related adverse reactions with coadministration of diltiazem. Solifenacin is significantly metabolized via the CYP3A4 pathway; diltiazem is a CYP3A4 inhibitor. Coadministration may result in increased concentrations of solifenacin.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and diltiazem; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and diltiazem is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
    Sotalol: (Moderate) The combination of diltiazem and a beta-blocker, like sotalol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of diltiazem and St. John's Wort due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable.
    Succinylcholine: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Sufentanil: (Moderate) Consider a reduced dose of sufentanil with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. If diltiazem is discontinued, consider increasing the sufentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a sensitive CYP3A4 substrate, and coadministration with a CYP3A4 inhibitor like diltiazem can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If diltiazem is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Sulindac: (Moderate) 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.
    Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with diltiazem. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with diltiazem increased the suvorexant AUC by 2-fold.
    Tacrolimus: (Moderate) Diltiazem inhibits tacrolimus metabolism via the CYP3A pathway. Tacrolimus blood concentrations should be monitored during concurrent diltiazem therapy as dosage adjustments of tacrolimus may be needed to avoid tacrolimus-induced toxicity.
    Tadalafil: (Moderate) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme. Inhibitors of CYP3A4, such as diltiazem, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with diltiazem is necessary. In clinical trials, coadministration with diltiazem increased talazoparib exposure by approximately 8%.
    Tamsulosin: (Moderate) 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.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and diltiazem. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as diltiazem, may increase exposure to tasimelteon with the potential for adverse reactions.
    Telithromycin: (Moderate) Telithromycin, a ketolide antibiotic, can compete with diltiazem for metabolism by CYP3A4. This can result in increased concentrations of diltiazem if the two drugs are coadministered.
    Temsirolimus: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with diltiazem; an increase in diltiazem-related adverse reactions may also occur. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering diltiazem. 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 CYP3A4; diltiazem is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
    Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
    Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with diltiazem; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor 100 mg/ivacaftor 150 mg tablet every other day in the morning and 1 ivacaftor 150 mg tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor 150 mg should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); diltiazem is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If diltiazem and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Thalidomide: (Moderate) Thalidomide and other agents that slow cardiac conduction such as calcium-channel blockers should be used cautiously due to the potential for additive bradycardia.
    Theophylline, Aminophylline: (Moderate) Diltiazem may inhibit the cytochrome P-450 metabolism of aminophylline. Since the therapeutic range is narrow for aminophylline, it is prudent to monitor aminophylline serum concentrations during diltiazem therapy. (Moderate) Diltiazem may inhibit the cytochrome P-450 metabolism of theophylline. Since the therapeutic range is narrow for theophylline, it is prudent to monitor theophylline serum concentrations during diltiazem therapy.
    Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Timolol: (Moderate) The combination of diltiazem and a beta-blocker, like timolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Tipranavir: (Moderate) Tipranavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4. Although drug interaction studies have not been conducted, the serum concentration of diltiazem may be increased with concomitant administration of tipranavir.
    Tolmetin: (Moderate) 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.
    Tolterodine: (Moderate) In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. CYP3A4 inhibitors include diltiazem.
    Tolvaptan: (Major) Avoid coadministration of diltiazem when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with diltiazem. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Topiramate: (Moderate) Coadministrator topiramate with diltiazem with caution. Concomitant administration of diltiazem (240 mg) with topiramate (150 mg/day) resulted in a 10% decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an 18% decrease in desacetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC of topiramate. Monitor for loss of diltiazem efficacy and or increased adverse events coming from the topiramate component of phentermine;topiramate.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and diltiazem is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and diltiazem 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/m2) 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: (Severe) 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: (Minor) 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: (Moderate) 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.
    Tretinoin, ATRA: (Moderate) Diltiazem may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA.
    Triazolam: (Moderate) Triazolam is metabolized by the cytochrome CYP3A4 enzyme and, as a result, is susceptible to drug interactions with drugs that can inhibit this enzyme, such as diltiazem. Patients receiving triazolam should be monitored for signs of an exaggerated response these drugs are used concomitantly.
    Tubocurarine: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and diltiazem is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Valdecoxib: (Moderate) 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: (Moderate) Vardenafil is metabolized by hepatic cytochrome P450 3A4. Inhibitors of CYP3A4, such as diltiazem, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.
    Vecuronium: (Moderate) Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with diltiazem due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of diltiazem. Venetoclax is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor.
    Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including severe myelosuppression, if coadministration with diltiazem is necessary. Vinblastine is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with diltiazem is necessary. Vinorelbine is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and diltiazem. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with diltiazem, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Moderate) 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 heart rate and blood pressure.
    Yohimbine: (Moderate) 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: (Minor) Zafirlukast and zileuton are respiratory antiinflammatory agents which can theoretically inhibit CYP3A4 metabolism of calcium-channel blockers, CYP3A4 substrates.
    Zileuton: (Minor) Zileuton is a respiratory antiinflammatory agent which can theoretically inhibit CYP3A4 metabolism of diltiazem, a CYP3A4 substrate.
    Ziprasidone: (Major) Diltiazem may reduce ziprasidone metabolism via inhibition of CYP3A4 isoenzymes. In addition, additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Zolpidem: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of diltiazem, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no well-controlled studies of diltiazem in pregnancy. Administer diltiazem to pregnant women only if the potential benefit justifies the potential risk to the fetus. Animal studies involving doses ranging from 5 to 10 times greater than the daily recommended therapeutic dose has resulted in embryo and fetal death. In some studies, skeletal abnormalities have been reported. At doses 20 times the human dose or greater there was an increase incidence of stillbirths.[28277]

    Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If diltiazem therapy is deemed essential to the mother, the manufacturer recommends an alternative method of infant feeding.[28277] However, the American Academy of Pediatrics generally considers the use of diltiazem to be usually compatible with breast-feeding. The AAP also considers verapamil, another calcium-channel blocker, to be usually compatible with breast-feeding.

    MECHANISM OF ACTION

    Diltiazem is similar to verapamil in that it inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. Calcium channels in myocardial and vascular smooth muscle cell membranes are selective and allow a slow, inward flow of calcium that contributes to excitation-contraction coupling and electrical discharge (plateau phase of the action potential) of conduction cells in the heart and vasculature. Diltiazem inhibits this influx, possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The resultant decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. In addition, total peripheral resistance, systemic blood pressure, and afterload are decreased. Diltiazem, like verapamil and nifedipine, effectively increases coronary blood flow. Therefore, calcium-channel blockers such as diltiazem are useful in managing angina and hypertension.
     
    The electrophysiologic effects of diltiazem make it a favorable agent for the temporary control of certain supraventricular arrhythmias and for the rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm. Diltiazem's inhibitory effects on conduction through the atrioventricular (AV) node is stronger than nifedipine's and similar to verapamil's. This is reflected on the ECG by a prolonged PR interval. Second- or third-degree heart block is possible, especially if diltiazem is given to patients receiving beta-blockers. Resting heart rate also can be decreased, especially in patients with sick sinus syndrome. Its effects on calcium channels in SA and AV nodes, and peripheral vasculature are equipotent. Diltiazem exerts fewer negative inotropic effects than either verapamil or nifedipine. Diltiazem is also less potent as a peripheral vasodilator than nifedipine and related dihydropyridine analogs. 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

    Diltiazem is administered orally and intravenously. It is widely distributed throughout the body and into maternal breast milk in equal concentrations to those achieved in serum. Roughly 70% to 80% of the circulating drug is bound to plasma proteins.
     
    About 10% to 35% of the absorbed dose is metabolized to deacetyldiltiazem, which has 25% to 50% of the coronary vasodilatory effects of diltiazem. The remaining metabolites are not pharmacologically active. Diltiazem exhibits dose-dependent kinetics, predisposing patients to accumulation with repeated dosing. The half-life ranges from 3.5 to 9 hours and is usually 4 to 6 hours. About 2% to 4% of the drug is excreted unchanged in the urine, with the remainder excreted in the bile and urine.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
    Diltiazem is an inhibitor and a substrate of CYP3A4. It has been postulated that N-demethylated metabolites of diltiazem are potent CYP3A4 inhibitors, and may contribute to the in vivo inhibitory effects of diltiazem with repeated dosing. Other drugs that are specific substrates, inhibitors, or inducers of CYP3A4 isoenzymes may interact with diltiazem. Patients taking other drugs that are CYP3A4 substrates, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping diltiazem.

    Oral Route

    Diltiazem is well absorbed after oral administration (roughly 80%). Extensive first-pass metabolism reduces bioavailability to 40% to 60%, with the upper range of bioavailability observed with the sustained-release products. The onset of action occurs within 1 hour for immediate-release products and within 2 to 3 hours for the sustained-release formulations of the drug. Time to peak effect is 2 to 3 hours for the immediate-release and 6 to 11 hours for the sustained-release formulations. The mean AUC of diltiazem is increased 50% in elderly vs. young subjects following oral administration. Grapefruit juice (food) appears to have no effect on diltiazem bioavailability, although the drug half-life is increased slightly.
     
    The sustained-release capsules should be taken whole, without opening, chewing, or crushing, because these actions can significantly alter the release characteristics of sustained-release products. The mean AUC of an extended-release diltiazem formulation is minimally (approximately 16%) higher when given to postprandial vs. fasting patients. Release of diltiazem from extended-release tablets is dependent on gastrointestinal transit times. The bioavailability of diltiazem extended-release tablets is unaffected by patient age.

    Intravenous Route

    Parenteral diltiazem is completely bioavailable. The onset of action occurs within minutes after IV administration, and the time to peak effect is 15 minutes. The mean AUC of diltiazem is increased 50% in elderly vs. young subjects after IV administration.