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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, TIADYLT ER, Tiazac

    HOW SUPPLIED

    Cardizem CD/Cardizem SR/Cartia XT/Dilacor XR/Dilt-CD/Diltia XT/Diltiazem/Diltiazem Hydrochloride/Diltzac/Taztia XT/TIADYLT ER/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, 1mg, 5mg

    DOSAGE & INDICATIONS

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

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

    Oral dosage (extended-release, once daily)
    Adults

    180 to 240 mg PO once daily, initially. May increase dose after 14 days if further control is needed. Usual dose range: 120 to 360 mg/day. Max: 540 mg/day.

    Oral dosage (extended-release, twice-daily)
    Adults

    60 to 120 mg PO twice daily, initially. May increase dose after 14 days if further control is needed. Usual dose range: 120 to 360 mg/day. Max: 360 mg/day.

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

    30 mg PO 4 times daily, initially. Gradually increase the dose every 1 to 2 days until desired clinical response is achieved. Usual dose: 180 to 360 mg/day in 3 to 4 divided doses.

    Oral dosage (extended-release capsules)
    Adults

    120 to 180 mg PO once daily, initially. Increase the dose every 7 to 14 days until desired clinical response is achieved. Max: 540 mg/day.

    Oral dosage (extended-release tablets)
    Adults

    180 mg PO once daily, initially. Increase the dose every 7 to 14 days until desired clinical response is achieved. Max: 360 mg/day.

    For the treatment of variant angina (Prinzmetal's angina).
    Oral dosage (immediate-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. Geriatric patients may need lower maximal dosage and slower titration. The usual dosage range is 180 to 360 mg/day. Max: 480 mg/day PO, given in 3 or 4 divided doses.

    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. In general, titrate dosage at 1- to 2-week intervals. Geriatric patients may need lower maximal dosage and slower titration. There is limited clinical experience with doses greater than 360 mg/day. Individual patients may respond to higher doses of up to 480 mg once daily. Usual Max: 480 mg/day PO for Cardizem CD; there is limited general clinical experience with doses above 360 mg, but doses to 540 mg have been studied in clinical trials. Max: 540 mg/day PO.

    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
    Infants older than 7 months†, Children†, and Adolescents†

    0.25 mg/kg IV bolus 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 once-daily 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
    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 (immediate-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. Geriatric patients may need lower initial and maximal dosages and slower titration. Max: 480 mg/day PO, in divided doses.

    For the treatment of idiopathic dilated cardiomyopathy†.
    Oral dosage (immediate-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. Geriatric patients may need lower initial and maximal dosages, and slower titration. 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.

    For the treatment of proteinuria† associated with diabetic nephropathy†.
    Oral dosage (e.g., sustained-release 12-hour dosage forms; i.e., Cardizem SR or generic equivalents)
    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 patients may need lower initial dosage and slower titration.

    For the treatment of anal fissures†.
    Intra-Anal dosage (2% ointment)
    Adults

    250 to 700 mg intra-anally every 12 hours for 6 to 12 weeks. Guidelines suggest topical calcium channel blockers as first-line therapy.

    For the treatment of pulmonary hypertension†.
    Oral dosage (immediate-release)
    Adults

    40 mg PO 3 times daily, initially. Increase dose to 80 to 240 mg PO 3 times daily as tolerated.

    Infants†, Children†, and Adolescents†

    0.5 mg/kg/dose PO 3 times daily, initially. Increase dose as tolerated. Usual dose: 3 to 5 mg/kg/day. Max: 360 mg/day.

    Oral dosage (extended-release, twice daily)
    Adults

    60 mg PO twice daily, initially. Increase dose to 120 to 360 mg PO twice daily as tolerated.

    Children† and Adolescents†

    0.75 mg/kg/dose PO twice daily, initially. Increase dose as tolerated. Usual dose: 3 to 5 mg/kg/day. Max: 360 mg/day.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

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

    Geriatric

    360 mg/day PO for diltiazem tablets and twice-daily extended-release capsules (e.g., Cardizem, Cardizem SR); 540 mg/day PO for hypertension for once-daily extended-release formulations (e.g., Dilacor-XR capsules, Tiazac capsules, Cardizem CD, 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 (Cardizem): Administer before meals and at bedtime. May be swallowed whole, crushed, or chewed; the 30 mg tablets should not be split; per the labeled instructions to patients, the medication is formulated to release slowly.[55768]
    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: 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 FDA-approved 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).[33119] 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).[33119]

    Injectable Administration

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

    Intravenous Administration

    Dilution
    Dilute in 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or 5% Dextrose and 0.45% Sodium Chloride Injection to to a final concentration of 0.45 to 1 mg/mL. A common infusion dilution is 125 mg of diltiazem injection added to 100 mL of an appropriate diluent, which yields a final concentration of 1 mg/mL.[45688]
    ASHP Recommended Standard Concentrations for Adult Continuous Infusions: 1 mg/mL.[64020]
    Storage: Refrigerate and use within 24 hours.[45688]
     
    IV Push
    No dilution necessary.
    Inject over 2 minutes.[45688]
     
    Continuous IV Infusion
    Infuse at an initial rate of 10 mg/hour, and increase if necessary to 15 mg/hour. Rates more than 15 mg/hour or infusions longer than 24 hours are not recommended.[45688]

    STORAGE

    Generic:
    - Protect from light
    - Store between 68 to 77 degrees F
    Cardizem:
    - Avoid excessive humidity
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Cardizem CD:
    - Avoid excessive humidity
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 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 between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Cartia XT :
    - Avoid excessive humidity
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Dilacor XR:
    - Avoid excessive humidity
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Dilt-CD :
    - Avoid excessive humidity
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Diltia XT:
    - Avoid excessive humidity
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Diltzac:
    - Avoid excessive humidity
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 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 between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    TIADYLT ER:
    - Avoid excessive humidity
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Tiazac:
    - Avoid excessive humidity
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 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. Doses ranging from 5 to 10 times greater than the daily recommended therapeutic human dose have resulted in embryo and fetal death in animal studies. In some animal studies, skeletal abnormalities have been reported. At doses 20 times the human dose or greater there was an increased incidence of stillbirths. Calcium channel blockers have generally not been well studied in human pregnancy for treating hypertension with the exception of nifedipine; data suggest extended-release nifedipine has no adverse effects on perinatal outcomes. Although diltiazem has been used with caution during pregnancy under specific circumstances, other medications are generally preferred over diltiazem during pregnancy for selected arrhythmias and other indications.

    Breast-feeding

    Diltiazem is excreted in human milk. Concentrations in human milk closely parallel maternal serum levels. If diltiazem therapy is deemed essential to the mother, the manufacturer recommends an alternative method of infant feeding. Data for use of diltiazem or verapamil during breast-feeding are limited. Nifedipine is usually considered compatible with breast-feeding.

    Geriatric

    In geriatric versus younger adult subjects, the half-life of diltiazem is prolonged, and clearance is decreased, with a potential increase in risk for drug accumulation and toxicity. In general, initiate at the lower end of the adult dosage range in the older adult and adjust diltiazem dosage based on clinical response.[28277] According to the Beers Criteria, non-dihydropyridine calcium channel blockers including diltiazem are considered potentially inappropriate medications (PIMs) 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.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; individualize the antihypertensive regimen to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. Calcium channel blockers may cause peripheral edema and clinically significant constipation; some agents may cause generalized aching, headache, and muscle pain. Antiarrhythmic agents can have serious adverse effects (e.g., changes in mental function, appetite, behavior, heart function, or increased risk for falls) in older individuals.[60742]

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 0-3.6
    AV block / Early / 0-3.3
    atrial fibrillation / Early / 0-2.0
    atrial flutter / Early / 0-2.0
    heart failure / Delayed / 0-2.0
    asystole / Rapid / 0-2.0
    peptic ulcer / Delayed / 0-2.0
    GI bleeding / Delayed / 0-2.0
    vasculitis / Delayed / 0-2.0
    ocular hemorrhage / Delayed / 0-2.0
    retinopathy / Delayed / 0-2.0
    renal failure (unspecified) / Delayed / 0-2.0
    ventricular tachycardia / Early / 0-1.0
    ventricular fibrillation / Early / 0-1.0
    toxic epidermal necrolysis / 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
    erythema multiforme / 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
    angina / Early / 0-2.0
    palpitations / Early / 0-2.0
    bundle-branch block / Early / 0-2.0
    sinus tachycardia / Rapid / 0-2.0
    chest pain (unspecified) / Early / 0-2.0
    colitis / Delayed / 0-2.0
    peripheral neuropathy / Delayed / 0-2.0
    amnesia / Delayed / 0-2.0
    confusion / Early / 0-2.0
    depression / Delayed / 0-2.0
    hallucinations / Early / 0-2.0
    hypertonia / Delayed / 0-2.0
    hyperuricemia / Delayed / 0-2.0
    hyperglycemia / Delayed / 0-2.0
    gout / Delayed / 0-2.0
    conjunctivitis / Delayed / 0-2.0
    amblyopia / Delayed / 0-2.0
    bone pain / Delayed / 0-2.0
    myopathy / Delayed / 0-2.0
    vaginitis / Delayed / 0-2.0
    cystitis / Delayed / 0-2.0
    nephrolithiasis / Delayed / 0-2.0
    elevated hepatic enzymes / Delayed / 0-1.0
    impotence (erectile dysfunction) / Delayed / 0-1.0
    peripheral vasodilation / Rapid / Incidence not known
    gingival hyperplasia / Delayed / 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
    abdominal pain / Early / 0-2.0
    weight gain / Delayed / 0-2.0
    eructation / Early / 0-2.0
    anorexia / Delayed / 0-2.0
    flatulence / Early / 0-2.0
    vomiting / Early / 0-2.0
    diarrhea / Early / 0-2.0
    dysgeusia / Early / 0-2.0
    xerostomia / Early / 0-2.0
    paresthesias / Delayed / 0-2.0
    tremor / Early / 0-2.0
    insomnia / Early / 0-2.0
    tinnitus / Delayed / 0-2.0
    vertigo / Early / 0-2.0
    drowsiness / Early / 0-2.0
    pruritus / Rapid / 0-2.0
    photosensitivity / Delayed / 0-2.0
    diaphoresis / Early / 0-2.0
    petechiae / Delayed / 0-2.0
    urticaria / Rapid / 0-2.0
    rash / Early / 1.0-2.0
    purpura / Delayed / 0-2.0
    alopecia / Delayed / 0-2.0
    otalgia / Early / 0-2.0
    ocular irritation / Rapid / 0-2.0
    muscle cramps / Delayed / 0-2.0
    arthralgia / 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) Use diltiazem and acebutolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    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 : (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; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like diltiazem can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If diltiazem is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. If diltiazem is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like diltiazem can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If diltiazem is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    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.
    Adenosine: (Moderate) Use adenosine with caution in the presence of calcium-channel blockers due to the potential for additive or synergistic depressant effects on the sinoatrial and atrioventricular nodes.
    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) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Alprazolam: (Major) Avoid coadministration of alprazolam and diltiazem due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with diltiazeml, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
    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.
    Aminolevulinic Acid: (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Amiodarone: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with amiodarone is necessary. Concurrent use may result in elevated diltiazem concentrations. Additive effects on cardiac contractility and/or AV conduction are also possible. Diltiazem is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor.
    Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with diltiazem is necessary. Atorvastatin is a CYP3A substrate; diltiazem is a CYP3A inhibitor. Concomitant use has been shown to increase atorvastatin overall exposure by 1.5-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Amlodipine; 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. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin and diltiazem, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving diltiazem therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure and heart rate. Diltiazem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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).
    Amphetamine; Dextroamphetamine Salts: (Minor) 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 is advised.
    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) Use of calcium-channel blockers and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination.
    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: (Major) Monitor blood pressure and for aripiprazole-related adverse reactions during concurrent use of diltiazem. Due to its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents; a diltiazem dose adjustment may be needed. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients also receiving a CYP2D6 inhibitor. Adults receiving a combination of a CYP2D6 inhibitor and diltiazem 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 weak or moderate CYP3A inhibitor alone. Aripiprazole is a substrate for CYP2D6 and CYP3A; diltiazem is a moderate CYP3A inhibitor.
    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.
    Articaine; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine.
    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; 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) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. If diltiazem is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like diltiazem can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If diltiazem is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    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) Use diltiazem and atenolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    Atenolol; Chlorthalidone: (Moderate) Use diltiazem and atenolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with diltiazem is necessary. Atorvastatin is a CYP3A substrate; diltiazem is a CYP3A inhibitor. Concomitant use has been shown to increase atorvastatin overall exposure by 1.5-fold.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with diltiazem is necessary. Atorvastatin is a CYP3A substrate; diltiazem is a CYP3A inhibitor. Concomitant use has been shown to increase atorvastatin overall exposure by 1.5-fold.
    Avanafil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving diltiazem. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
    Avapritinib: (Major) Avoid coadministration of avapritinib with diltiazem due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
    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.
    Bendroflumethiazide; Nadolol: (Moderate) Use diltiazem and nadolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with diltiazem may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of diltiazem in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Diltiazem is an inhibitor of CYP3A4.
    Benzphetamine: (Minor) Benzphetamine might 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 is advised.
    Berotralstat: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with berotralstat is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
    Betaxolol: (Moderate) Use diltiazem and betaxolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    Bisoprolol: (Moderate) Use diltiazem and bisoprolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Use diltiazem and bisoprolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    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: (Major) Avoid coadministration of diltiazem and bosentan if possible due to decreased plasma concentrations of diltiazem; additionally, increased plasma concentrations of bosentan may occur. If coadministration unavoidable, monitor blood pressure and heart rate and adjust the diltiazem and bosentan dose based on clinical response. Diltiazem is a CYP3A4 substrate and inhibitor; bosentan is a CYP3A4 substrate and moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased diltiazem exposure by 69% and decreased exposure to desacetyldiltiazem by 75%.
    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.
    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: (Major) Avoid coadministration of brigatinib with diltiazem if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of diltiazem, resume the brigatinib dose that was tolerated prior to initiation of diltiazem. Brigatinib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Brimonidine; Timolol: (Moderate) Monitor blood pressure and heart rate during concomitant diltiazem and timolol use; dosage adjustments may be needed. Concomitant use may result in additive effects in prolonging AV conduction and additive antihypertensive effects.
    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; 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.
    Brompheniramine; 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; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (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.
    Budesonide; Glycopyrrolate; 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; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine. (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.
    Bupivacaine; Meloxicam: (Moderate) Diltiazem may inhibit the CYP3A4-mediated metabolism of bupivacaine. Use caution when administering these drugs concomitantly. (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.
    Buprenorphine: (Moderate) Concomitant use of buprenorphine and diltiazem can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when diltiazem is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping diltiazem, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If diltiazem is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and diltiazem is a CYP3A4 inhibitor.
    Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and diltiazem can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when diltiazem is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping diltiazem, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If diltiazem is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and diltiazem is a CYP3A4 inhibitor.
    Buspirone: (Moderate) Monitor for an increase in buspirone-related adverse reactions if coadministration with diltiazem is necessary; the effect may be more pronounced if the patient has been titrated to a stable dose of buspirone and diltiazem is added or removed from therapy. Buspirone is a sensitive CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors increased buspirone exposure by 3.4 to 6-fold and was accompanied by increased buspirone-related adverse reactions.
    Butalbital; Acetaminophen; 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.
    Cabergoline: (Moderate) Cabergoline should be used cautiously with antihypertensive agents, including diltiazem. Cabergoline has been associated with hypotension. Initial doses of carbergoline higher than 1 mg may produce orthostatic hypotension. It may be advisable to monitor blood pressure.
    Cabotegravir; 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.
    Carbamazepine: (Major) Avoid coadministration of diltiazem and carbamazepine due to decreased plasma concentrations of diltiazem. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable levels. Concomitant use has also resulted in a 40% to 72% increase in carbamazepine plasma concentration leading to toxicity in some cases. Diltiazem is a substrate and moderate inhibitor of CYP3A4 substrate and carbamazepine is a substrate and strong inducer of CYP3A4.
    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; 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) Use diltiazem and carvedilol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. Monitor ECG and blood pressure if diltiazem is coadministered with carvedilol.
    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.
    Celecoxib; Tramadol: (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.
    Cenobamate: (Moderate) Avoid coadministration of diltiazem and cenobamate 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 cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased diltiazem exposure by 69% and decreased exposure to desacetyldiltiazem by 75%.
    Ceritinib: (Major) Avoid concomitant use of ceritinib with diltiazem if possible due to the risk of additive bradycardia; diltiazem exposure may also increase. Both ceritinib and diltiazem can cause bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Monitor blood pressure and heart rate. Diltiazem is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Cetirizine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    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; Amitriptyline: (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; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    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; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like diltiazem can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If diltiazem is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; 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.
    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) Avoid concomitant use of diltiazem and extended-release clonidine tablets. Monitor heart rate during concomitant use of diltiazem and other clonidine formulations. Concomitant use may potentiate bradycardia and risk of AV block. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported during the use of diltiazem and clonidine.
    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%.
    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) Monitor blood pressure and heart rate if coadministration of diltiazem with ciprofloxacin is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A substrate and ciprofloxacin is a moderate CYP3A inhibitor.
    Cisapride: (Contraindicated) 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.
    Clarithromycin: (Major) Avoid coadministration of clarithromycin and diltiazem, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving diltiazem therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure and heart rate. Diltiazem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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).
    Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with diltiazem; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor.
    Clonidine: (Moderate) Avoid concomitant use of diltiazem and extended-release clonidine tablets. Monitor heart rate during concomitant use of diltiazem and other clonidine formulations. Concomitant use may potentiate bradycardia and risk of AV block. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported during the use of diltiazem and clonidine.
    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.
    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.
    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; Guaifenesin; Pseudoephedrine: (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) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    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 a moderate CYP3A4 inhibitor like 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: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with conivaptan is necessary. Concurrent use may result in elevated diltiazem concentrations and additive risk for hypotension. Diltiazem is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    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.
    Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with diltiazem. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Concomitant use of diltiazem increased daridorexant overall exposure 2.4-fold in drug interaction studies.
    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: (Moderate) Ritonavir is expected to decrease 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. A decreased diltiazem dose 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.
    Desogestrel; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Dexbrompheniramine; 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.
    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) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with diltiazem is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and diltiazem is a CYP3A inhibitor.
    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) Measure serum digoxin concentrations before initiating diltiazem. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring. In addition, coadministration of digoxin with calcium channel blockers may produce additive effects on AV node conduction resulting in bradycardia and advanced or complete heart block. Coadministration of digoxin and diltiazem increases the serum concentration of digoxin by 20%.
    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) Monitor blood pressure and heart rate during concomitant diltiazem and timolol use; dosage adjustments may be needed. Concomitant use may result in additive effects in prolonging AV conduction and additive antihypertensive effects.
    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 Liposomal: (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.
    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 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.
    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.
    Elagolix; Estradiol; Norethindrone acetate: (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. (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.
    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.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the elexacaftor; tezacaftor; ivacaftor dosing schedule when coadministered with diltiazem; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor; tezacaftor; ivacaftor combination tablets every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., elexacaftor; tezacaftor; ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive CYP3A4 substrate); diltiazem is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased ivacaftor exposure by 3-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2-fold, respectively. (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; ivacaftor combination tablet every other day in the morning and 1 ivacaftor 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 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.
    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.
    Elvitegravir; Cobicistat; 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.
    Elvitegravir; Cobicistat; 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.
    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; Linagliptin; 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.
    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.
    Entrectinib: (Major) Avoid coadministration of entrectinib with diltiazem due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If diltiazem is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of diltiazem. Entrectinib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    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 levels.
    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.
    Ephedrine; Guaifenesin: (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.
    Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine.
    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.
    Ergot alkaloids: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of diltiazem is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and diltiazem is a moderate CYP3A inhibitor.
    Erythromycin: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with erythromycin is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor.
    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: (Major) Esmolol is contraindicated with intravenous diltiazem use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving esmolol and another cardiodepressant calcium channel blocker. Use esmolol and oral diltiazem with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    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.
    Estradiol; Progesterone: (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. (Minor) The metabolism of progesterone may be decreased by inhibitors of cytochrome P450 3A4 hepatic enzymes, such as diltiazem.
    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) Advise patients to avoid alcohol consumption while taking diltiazem; there may be additive effects on blood pressure that may increase the risk for orthostatic hypotension, dizziness or syncope. Alcohol also 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; 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; 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.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    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.
    Etonogestrel; Ethinyl Estradiol: (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.
    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: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with diltiazem is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Diltiazem is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    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 CYP3A metabolism by diltiazem.
    Fedratinib: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with fedratinib is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor.
    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 CYP3A4 substrate, and coadministration with CYP3A4 inhibitors 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.
    Fexofenadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Finasteride; Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with diltiazem is necessary. Tadalafil is a CYP3A4 substrate and diltiazem is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or diltiazem; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
    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) 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: (Moderate) Limit use of flecainide and diltiazem when possible, and do not exceed maximum daily doses. Coadministration of flecainide with diltiazem increases the risk of bradycardia, AV block, and hypotension.
    Flibanserin: (Contraindicated) 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) Monitor blood pressure and heart rate if coadministration of diltiazem with fluconazole is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
    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.
    Fosamprenavir: (Moderate) Monitor blood pressure, heart rate, and for increased fosamprenavir-related adverse reactions if concurrent use of diltiazem and fosamprenavir is necessary. Concomitant use may increase the exposure of both drugs. Diltiazem and fosamprenavir are both CYP3A substrates and moderate CYP3A inhibitors.
    Fosphenytoin: (Major) Avoid coadministration of diltiazem and fosphenytoin due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable.
    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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like diltiazem can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If diltiazem is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like diltiazem can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If diltiazem is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (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.
    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.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like diltiazem can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If diltiazem is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    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.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like diltiazem can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If diltiazem is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like diltiazem can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If diltiazem is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (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; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like diltiazem can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If diltiazem is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Ibrutinib: (Major) If ibrutinib is coadministered with diltiazem, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if diltiazem is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    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; Famotidine: (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) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. If diltiazem is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like diltiazem can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If diltiazem is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (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.
    Infigratinib: (Major) Avoid concomitant use of infigratinib and diltiazem. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    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. Caution is recommended when administering these medications 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: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of diltiazem is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor.
    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) Monitor blood pressure and heart rate if coadministration of diltiazem with ketoconazole is necessary. Concurrent use may result in elevated diltiazem concentrations. An adjustment in the diltiazem dose may be warranted. Diltiazem is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    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: (Major) Intravenous labetalol is contraindicated with intravenous diltiazem use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving intravenous beta-blockers and intravenous calcium channel blockers. Use oral labetalol and oral diltiazem with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    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; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin and diltiazem, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving diltiazem therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure and heart rate. Diltiazem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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).
    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: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with lapatinib is necessary. Diltiazem is a CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor.
    Lasmiditan: (Moderate) Monitor heart rate if lasmiditan is coadministered with calcium-channel blockers as concurrent use may increase the risk for bradycardia. Lasmiditan has been associated with lowering of heart rate. In a drug interaction study, addition of a single 200 mg dose of lasmiditan to another heart rate lowering drug decreased heart rate by an additional 5 beats per minute.
    Lefamulin: (Moderate) Monitor for lefamulin- or diltiazem-related adverse effects if oral lefamulin is administered with diltiazem as concurrent use may increase exposure from both drugs; an interaction is not expected with intravenous lefamulin. Both drugs are substrates and moderate inhibitors of CYP3A4.
    Lemborexant: (Major) Avoid coadministration of lemborexant and diltiazem as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
    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.
    Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Levoketoconazole: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with ketoconazole is necessary. Concurrent use may result in elevated diltiazem concentrations. An adjustment in the diltiazem dose may be warranted. Diltiazem is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Levonorgestrel; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    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.
    Lidocaine; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine. (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.
    Lidocaine; Prilocaine: (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: (Minor) Lisdexamfetamine might 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 is advised.
    Lithium: (Moderate) Monitor for neurologic adverse reactions during concomitant use of lithium and calcium channel blockers. Concomitant use may increase the risk of neurologic adverse reactions, such as ataxia, tremors, nausea, vomiting, diarrhea, and/or tinnitus.
    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: (Contraindicated) 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.
    Lonafarnib: (Contraindicated) Coadministration of lonafarnib and diltiazem is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; diltiazem is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
    Lopinavir; Ritonavir: (Moderate) Ritonavir is expected to decrease 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. A decreased diltiazem dose may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration.
    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.
    Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of diltiazem is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration with diltiazem increased the lumateperone AUC by approximately 2-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.
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and diltiazem due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor.
    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.
    Mavacamten: (Major) Avoid coadministration of diltiazem and mavacamten 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. Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting diltiazem therapy. Avoid initiation of diltiazem in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable diltiazem therapy. Expect additive negative inotropic effects during concomitant use of mavacamten and diltiazem. If concomitant therapy with diltiazem is initiated, or if the dose is increased, monitor left ventricular ejection fraction closely until stable doses and clinical response have been achieved. Avoid concomitant use of mavacamten with disopyramide in combination with diltiazem due to association with left ventricular systolic dysfunction and heart failure symptoms. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a substrate and moderate inducer of CYP3A and diltiazem is a substrate and moderate inhibitor of CYP3A. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of mavacamten with diltiazem in CYP2C19 poor metabolizers is predicted to increase mavacamten exposure up to 55%. Coadministration with another moderate CYP3A inducer decreased diltiazem exposure by 69% and decreased exposure to desacetyldiltiazem by 75%.
    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) Monitor blood pressure during concomitant calcium-channel blocker and melatonin use. Melatonin may impair the efficacy of calcium-channel blockers. In a 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 a calcium channel blocker Melatonin appeared to antagonize the antihypertensive effects of the calcium channel blocker.
    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: (Minor) 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 is advised.
    Methoxsalen: (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylphenidate Derivatives: (Moderate) Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate derivatives and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate derivatives. Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents, including calcium-channel blockers.
    Methylprednisolone: (Moderate) Monitor for corticosteroid-related adverse events if methylprednisolone is used with diltiazem. Concurrent use has been observed to increase methylprednisolone peak exposure, overall exposure, and half-life by 1.6-, 2.6-, and 1.9-fold, respectively.
    Metoprolol: (Major) Intravenous metoprolol is contraindicated with intravenous diltiazem use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving intravenous beta-blockers and intravenous calcium channel blockers. Use oral metoprolol and oral diltiazem with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Major) Intravenous metoprolol is contraindicated with intravenous diltiazem use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving intravenous beta-blockers and intravenous calcium channel blockers. Use oral metoprolol and oral diltiazem with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    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 due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and diltiazem is a CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
    Mifepristone: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with mifepristone is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with diltiazem and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
    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.
    Mobocertinib: (Major) Avoid concomitant use of mobocertinib and diltiazem; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions. Mobocertinib is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
    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) Use diltiazem and nadolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    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: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with diltiazem is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with diltiazem is necessary. The dose of sirolimus may also need to be reduced with coadministration of diltiazem. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of diltiazem. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; diltiazem is a moderate CYP3A inhibitor. Overall sirolimus exposure was increased 1.6-fold when coadministered with diltiazem.
    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; Esomeprazole: (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.
    Nebivolol: (Moderate) Monitor blood pressure and heart rate during concomitant diltiazem and nebivolol use; dosage adjustments may be needed. Concomitant use may result in additive effects in prolonging AV conduction and additive antihypertensive effects.
    Nebivolol; Valsartan: (Moderate) Monitor blood pressure and heart rate during concomitant diltiazem and nebivolol use; dosage adjustments may be needed. Concomitant use may result in additive effects in prolonging AV conduction and additive antihypertensive effects.
    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) Concomitant use of neuromuscular blockers and calcium-channel blockers may prolong neuromuscular blockade.
    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 CYP3A 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 diltiazem with nilotinib is necessary; also monitor for nilotinib-related side effects. Nilotinib and diltiazem 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.
    Nirmatrelvir; Ritonavir: (Moderate) Ritonavir is expected to decrease 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. A decreased diltiazem dose may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration.
    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.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Norethindrone; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Norgestimate; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    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.
    Olanzapine; Fluoxetine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olanzapine; Samidorphan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olaparib: (Major) Avoid coadministration of olaparib with diltiazem due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after diltiazem is discontinued. Olaparib is a CYP3A substrate and diltiazem is a moderate CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
    Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and diltiazem is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and diltiazem may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If diltiazem is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir is expected to decrease 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. A decreased diltiazem dose may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration.
    Omeprazole; Amoxicillin; 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.
    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.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. If diltiazem is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like diltiazem can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If diltiazem is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    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.
    Ozanimod: (Major) Treatment with ozanimod should generally not be initiated in patients who are concurrently treated with both a heart rate lowering calcium channel blocker (e.g., diltiazem) and a beta blocker. If treatment initiation with ozanimod is considered in patients on both a heart rate lowering calcium channel blocker and beta blocker, advice from a cardiologist should be sought.
    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.
    Pacritinib: (Major) Avoid concurrent use of pacritinib with diltiazem due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor.
    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 paliperidone and calcium-channel blockers who are susceptible to hypotension.
    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.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and diltiazem due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If diltiazem is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of diltiazem. Pemigatinib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
    Penbutolol: (Moderate) Use diltiazem and penbutolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    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) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with diltiazem as concurrent use may increase pexidartinib exposure and the risk of adverse events; additionally, decreased plasma concentrations of diltiazem may occur. If concurrent use cannot be avoided, reduce the dose of pexidartinib as follows: 800 mg/day or 600 mg/day of pexidartinib, reduce to 200 mg twice daily; 400 mg/day of pexidartinib, reduce to 200 mg once daily. Monitor blood pressure and heart rate and adjust the diltiazem dose based on clinical response. If diltiazem is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of diltiazem. Pexidartinib is a moderate CYP3A4 inducer and CYP3A4 substrate; diltiazem is a moderate CYP3A inhibitor and CYP3A4 substrate. Based on modeling and simulation data, coadministration with another moderate CYP3A inhibitor was predicted to increase the pexidartinib exposure by 67%.
    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) Monitor for loss of diltiazem efficacy and an increase in topiramate-related adverse events during coadministration. Concomitant use 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.
    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.
    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 (topical): (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Pimozide: (Contraindicated) 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) Use diltiazem and pindolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    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.
    Ponesimod: (Major) Avoid concomitant use of ponesimod and medications that may decrease heart rate such as diltiazem due to the risk for severe bradycardia and heart block. Consider consultation from a cardiologist if concomitant use is necessary.
    Posaconazole: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with posaconazole is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor.
    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.
    Prilocaine; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine.
    Probenecid; 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 a moderate CYP3A4 inhibitor like 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.
    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.
    Promethazine; 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.
    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: (Major) Intravenous propranolol is contraindicated with intravenous diltiazem use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving intravenous beta-blockers and intravenous calcium channel blockers. Use oral propranolol and oral diltiazem with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted. Administration of diltiazem concomitantly with propranolol in 5 normal volunteers resulted in increased propranolol concentrations in all subjects, and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its binding sites by diltiazem.
    Propranolol; Hydrochlorothiazide, HCTZ: (Major) Intravenous propranolol is contraindicated with intravenous diltiazem use in close proximity (within a few hours). Fatal cardiac arrests have occurred in patients receiving intravenous beta-blockers and intravenous calcium channel blockers. Use oral propranolol and oral diltiazem with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted. Administration of diltiazem concomitantly with propranolol in 5 normal volunteers resulted in increased propranolol concentrations in all subjects, and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its binding sites by diltiazem.
    Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Pseudoephedrine; Triprolidine: (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.
    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.
    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: (Contraindicated) 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.
    Relugolix; Estradiol; Norethindrone acetate: (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.
    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: (Major) Avoid coadministration of diltiazem and rifapentine due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable levels.
    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.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with diltiazem; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    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: (Moderate) Ritonavir is expected to decrease 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. A decreased diltiazem dose may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration.
    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.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Coadministration of segesterone, a CYP3A4 substrate and moderate CYP3A4 inhibitors such as diltiazem may increase the serum concentration of segesterone. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib and diltiazem due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If diltiazem is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of diltiazem. Selpercatinib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with diltiazem is predicted to increase selpercatinib exposure by 60% to 99%.
    Selumetinib: (Major) Avoid coadministration of selumetinib and diltiazem due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If diltiazem is discontinued, resume the original selumetinib dose after 3 elimination half-lives of diltiazem. Selumetinib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
    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; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration with a moderate CYP3A4 inhibitor increased the Cmax and AUC of sildenafil by 160% and 182%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A4 inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
    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 CYP3A 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 CYP3A 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.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving diltiazem due to the potential for additive effects on heart rate. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Additionally, concomitant use of siponimod and diltiazem may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
    Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with diltiazem is necessary. The dose of sirolimus may also need to be reduced with coadministration of diltiazem. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of diltiazem. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; diltiazem is a moderate CYP3A inhibitor. Overall sirolimus exposure was increased 1.6-fold when coadministered with diltiazem.
    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) Monitor blood pressure and heart rate during concomitant diltiazem and sotalol use; dosage adjustments may be needed. Concomitant use may result in additive effects in prolonging AV conduction and additive antihypertensive effects.
    Sotorasib: (Moderate) Avoid coadministration of diltiazem and sotorasib 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 sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased diltiazem exposure by 69% and decreased exposure to desacetyldiltiazem by 75%.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of diltiazem and St. John's wort if possible due to the potential for 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.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if diltiazem must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. If diltiazem is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a moderate 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.
    Sumatriptan; 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.
    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) Monitor for an increase in tadalafil-related adverse reactions if coadministration with diltiazem is necessary. Tadalafil is a CYP3A4 substrate and diltiazem is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
    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.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with diltiazem as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If diltiazem is discontinued, wait at least 3 half-lives of diltiazem before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
    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.
    Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
    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; ivacaftor combination tablet every other day in the morning and 1 ivacaftor 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 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) Monitor blood pressure and heart rate during concomitant diltiazem and timolol use; dosage adjustments may be needed. Concomitant use may result in additive effects in prolonging AV conduction and additive antihypertensive effects.
    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) Monitor for loss of diltiazem efficacy and an increase in topiramate-related adverse events during coadministration. Concomitant use 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.
    Tranylcypromine: (Major) Avoid concomitant use of calcium-channel blockers and tranylcypromine due to the risk of additive hypotension. Potential for this interaction persists for up to 10 days after discontinuation of tranylcypromine (or 4 to 5 half-lives after discontinuation of the calcium-channel blocker). If a medication-free interval is not feasible, initiate therapy at the lowest appropriate dose and monitor blood pressure closely.
    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.
    Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with diltiazem; consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    Tucatinib: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with tucatinib is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
    Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with diltiazem. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
    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: (Major) Do not use vardenafil orally disintegrating tablets with diltiazem due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Additive effects on blood pressure are also possible. Vardenafil is primarily metabolized by CYP3A and diltiazem is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the AUC of vardenafil by 4-fold.
    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.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with calcium channel blockers is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use with calcium channel blockers could enhance the rate of verteporfin uptake by the vascular endothelium, resulting in enhanced photosensitivity.
    Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with diltiazem is necessary. Vinblastine is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another 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.
    Voclosporin: (Major) Reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening if coadministered with diltiazem. Concomitant use may increase voclosporin exposure and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors is predicted to increase voclosporin exposure by 3-fold.
    Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin and diltiazem, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving diltiazem therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure and heart rate. Diltiazem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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).
    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) Monitor blood pressure and heart rate if coadministration of diltiazem with voriconazole is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
    Voxelotor: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with voxelotor is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with diltiazem is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Diltiazem is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Zafirlukast: (Minor) Zafirlukast and zileuton are respiratory antiinflammatory agents which can theoretically inhibit CYP3A4 metabolism of calcium-channel blockers, CYP3A4 substrates.
    Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with diltiazem. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of diltiazem, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% when coadministered with diltiazem.
    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.

    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. Doses ranging from 5 to 10 times greater than the daily recommended therapeutic human dose have resulted in embryo and fetal death in animal studies. In some animal studies, skeletal abnormalities have been reported. At doses 20 times the human dose or greater there was an increased incidence of stillbirths. Calcium channel blockers have generally not been well studied in human pregnancy for treating hypertension with the exception of nifedipine; data suggest extended-release nifedipine has no adverse effects on perinatal outcomes. Although diltiazem has been used with caution during pregnancy under specific circumstances, other medications are generally preferred over diltiazem during pregnancy for selected arrhythmias and other indications.

    Diltiazem is excreted in human milk. Concentrations in human milk closely parallel maternal serum levels. If diltiazem therapy is deemed essential to the mother, the manufacturer recommends an alternative method of infant feeding. Data for use of diltiazem or verapamil during breast-feeding are limited. Nifedipine is usually considered 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.