Diltiazem
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Hypertension | Adults | Monotherapy or combination (oral ER) | FDA Approved |
| Chronic stable angina | Adults | Monotherapy or with nitrates/beta-blockers (oral) | FDA Approved |
| Vasospastic angina (Prinzmetal) | Adults | Monotherapy (oral) | FDA Approved |
| Atrial fibrillation / flutter — rate control | Adults | Acute IV rate control | FDA Approved |
| Paroxysmal supraventricular tachycardia (PSVT) | Adults | Acute IV conversion | FDA Approved |
Diltiazem is a versatile non-dihydropyridine calcium channel blocker with both vascular and cardiac electrophysiological effects, giving it a uniquely broad indication profile among CCBs. Unlike dihydropyridines (which are predominantly vasodilators), diltiazem slows AV nodal conduction and reduces heart rate, making it effective for both angina and supraventricular arrhythmias in addition to hypertension. It decreases vascular resistance, reduces cardiac afterload, and directly dilates coronary arteries while simultaneously slowing the sinoatrial and atrioventricular nodes.
Atrial fibrillation / flutter — chronic oral rate control — widely used orally for ongoing rate control in AF; supported by ACC/AHA/HRS guidelines as a first-line rate-control agent (Evidence: High)
Migraine prophylaxis — considered as an alternative preventive agent when first-line therapies are contraindicated or ineffective (Evidence: Moderate)
Anal fissure — topical 2% diltiazem ointment reduces anal sphincter pressure and promotes fissure healing (Evidence: Moderate)
Pulmonary arterial hypertension — used in vasoreactive patients who respond to acute vasodilator testing; less preferred than nifedipine or amlodipine (Evidence: Low)
Dosing
Adult Oral Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Hypertension — ER once-daily (CD/Cartia XT type) | 180–240 mg once daily | 120–320 mg once daily | 480 mg/day | Titrate at 7–14 day intervals; max antihypertensive effect by ~14 days Cardizem CD, Cartia XT, Dilt-CD formulations |
| Hypertension — ER once-daily (LA/Tiazac type) | 180–240 mg once daily | 120–320 mg once daily | 540 mg/day | Some patients respond to lower starting doses Cardizem LA, Tiazac, Taztia XT, Matzim LA, Dilacor XR |
| Chronic stable angina — IR tablets | 30 mg QID | 180–360 mg/day divided Q6–8h | 360 mg/day | Titrate every 1–2 days until angina controlled; take before meals and at bedtime |
| Chronic stable angina — ER once-daily (CD type) | 120–180 mg once daily | 120–320 mg once daily | 480 mg/day | Titrate at 7–14 day intervals based on angina frequency |
| Chronic stable angina — ER once-daily (LA type) | 180 mg once daily | Up to 360 mg once daily | 360 mg/day | Titrate at 7–14 day intervals |
| AF/AFL rate control — chronic oral (off-label) | 120–180 mg ER once daily | 120–360 mg/day | 360 mg/day (ER) | ACC/AHA/HRS guideline first-line rate-control agent; use same total daily dose when converting IR to ER |
IV Dosing — Acute Arrhythmia Management
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| AF/AFL — acute IV rate control | 0.25 mg/kg IV bolus over 2 min (typical 20 mg for 80 kg patient) | Infusion: 5–15 mg/h | 15 mg/h; max 24 h infusion | If initial bolus inadequate at 15 min: repeat 0.35 mg/kg (typical 25 mg) over 2 min; transition to oral as soon as feasible |
| PSVT — acute conversion | 0.25 mg/kg IV bolus over 2 min | Repeat 0.35 mg/kg if needed after 15 min | As above | Adenosine is typically first-line; diltiazem used if adenosine fails or is contraindicated |
Special Population Dosing
| Population | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Hepatic impairment | Lowest available dose | Individualize | Reduced | AUC increased 69% in cirrhosis; half-life prolonged; monitor closely |
| Renal impairment | Standard dosing | Standard | Standard | No significant PK changes; not removed by hemodialysis |
| Elderly | Lower end of range | Titrate cautiously | Standard | More sensitive to bradycardia and hypotensive effects; start low, go slow |
Diltiazem is marketed in numerous ER formulations that differ in release characteristics, dosing frequency, and maximum doses. Cardizem CD, Cartia XT, and Dilt-CD are once-daily capsules (max 480 mg/day). Cardizem LA and Matzim LA are once-daily tablets (max 540 mg/day for HTN, 360 mg for angina). Cardizem SR is a twice-daily capsule (max 360 mg/day). Dilacor XR and Tiazac are once-daily capsules (max 540 mg/day). These formulations should not be substituted without verifying bioequivalence and adjusting the dose accordingly. When converting from IR to ER, use the same total daily dose but confirm the appropriate ER formulation and its specific maximum.
Pharmacology
Mechanism of Action
Diltiazem inhibits the influx of calcium ions through L-type voltage-gated calcium channels in both vascular smooth muscle and cardiac myocytes. Unlike dihydropyridine CCBs (which act primarily on vascular smooth muscle), diltiazem has clinically significant effects on the heart’s conduction system. It slows conduction through the sinoatrial and atrioventricular nodes, reduces heart rate, and prolongs AV nodal refractoriness — properties that underpin its anti-arrhythmic efficacy. Simultaneously, diltiazem dilates coronary arteries and peripheral arterioles, reducing both afterload and myocardial oxygen demand. The dual vascular-and-nodal mechanism distinguishes diltiazem from dihydropyridines (which cause reflex tachycardia) and from verapamil (which has stronger negative inotropy). Diltiazem also reduces the renal and peripheral effects of angiotensin II and has a mild early natriuretic effect.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | ~98% absorbed from GI tract; bioavailability ~40% due to first-pass metabolism; ER (CD) Tmax 10–14 h; >95% absorbed from ER formulations relative to IR | Significant first-pass effect makes diltiazem sensitive to CYP3A4 interactions and hepatic impairment. Alcohol increases rate of release from CD formulation. Food does not significantly affect ER absorption. |
| Distribution | Protein binding 70–80%; competitive binding not altered by digoxin, HCTZ, propranolol, warfarin, or salicylic acid at therapeutic concentrations | Moderate protein binding. Diltiazem has a negative inotropic effect in isolated tissue but this is rarely clinically significant in patients with normal ventricular function. |
| Metabolism | Hepatic via CYP3A4 (both substrate and inhibitor); active metabolite desacetyldiltiazem (25–50% potency of parent, levels 10–20% of parent); non-linear PK: half-life slightly increases with dose | Dual role as CYP3A4 substrate and inhibitor creates bidirectional interaction potential. Hepatic impairment increases AUC by 69% and prolongs half-life. Desacetyldiltiazem contributes to both therapeutic and adverse effects. |
| Elimination | Primarily renal and fecal as metabolites; t½ 3.0–4.5 h (oral); therapeutic plasma range 50–200 ng/mL; not removed by hemodialysis | Short half-life requires multiple daily dosing for IR or use of ER formulations. Renal impairment does not alter PK. Plasmapheresis or charcoal hemoperfusion may help in overdose. |
Side Effects
Adverse effect data below are from controlled clinical trials of oral diltiazem formulations (approximately 3,000 patients treated). Side effects from IR angina trials (Cardizem) and ER angina trials (Cardizem LA) are presented separately where data differ by formulation.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Peripheral edema | Up to 15% (ER, dose-dependent) | Dose- and formulation-related: 2.4% with IR angina trials, 6.8% lower-limb edema in Cardizem LA angina study. Localized vasodilatory effect. Less prominent than with dihydropyridines at comparable BP-lowering doses. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dizziness | 6.4% (Cardizem LA); 1.5% (IR) | More common with ER formulations at higher doses; dose-dependent; advise slow position changes |
| Fatigue / asthenia | 4.8% (Cardizem LA); 1.2% (IR) | Related to reduced cardiac output and lower heart rate; generally mild |
| Bradycardia | 3.6% (Cardizem LA) | Expected pharmacologic effect from AV nodal depression; more likely with concurrent beta-blocker or digoxin. First-degree AV block 3.2% in same study. |
| Headache | 2.1% (IR angina trials) | Vasodilatory mechanism; usually self-limiting in the first week |
| Nausea | 1.9% (IR angina trials) | Take IR tablets with food if GI discomfort occurs |
| Cough | 2.0% (Cardizem LA angina study) | Distinguish from ACE-inhibitor cough; mechanism unclear |
| Rash | 1.3% (IR angina trials) | Monitor for progression; rare cases of SJS/TEN and leukocytoclastic vasculitis reported post-marketing |
| Constipation | ~2–3% | More common than with dihydropyridines; related to GI smooth muscle calcium channel blockade |
| Flushing | <1% (IR trials) | Much less common than with dihydropyridines; due to more balanced vascular-cardiac selectivity |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Second/third-degree AV block | 0.40% (13/3290 patients) | Days to weeks; higher risk with sick sinus syndrome | Hold diltiazem; ECG; may require temporary pacing; contraindicated without functioning pacemaker |
| Symptomatic bradycardia | Uncommon | Early therapy or dose escalation | Reduce dose or hold; atropine for acute episodes; assess for concurrent rate-slowing drugs |
| Asystole | Very rare | Reported after single 60 mg dose in a Prinzmetal angina patient | Emergency resuscitation; permanent discontinuation; IV calcium, atropine, pacing |
| Worsening heart failure | Rare | Weeks to months; higher risk with impaired LV function | Monitor for volume overload; discontinue diltiazem; standard HF management |
| Acute hepatic injury | Rare | 1–8 weeks after initiation | Check LFTs; discontinue immediately; usually reversible upon cessation |
| Stevens-Johnson syndrome / TEN | Very rare (post-marketing) | Days to weeks | Immediate discontinuation; dermatology consult; supportive care |
Diltiazem intentionally slows heart rate as part of its therapeutic mechanism, particularly for angina and rate control in atrial fibrillation. Clinical judgment is required to distinguish between therapeutic rate reduction and pathologic bradycardia. A resting heart rate of 50–60 bpm in an otherwise asymptomatic patient on diltiazem is often acceptable and expected. Symptomatic bradycardia (fatigue, dizziness, presyncope) or heart rate below 50 bpm warrants dose reduction. Regular ECG monitoring is essential, particularly when diltiazem is combined with beta-blockers or digoxin.
Drug Interactions
Diltiazem is both a substrate and a moderate inhibitor of CYP3A4 and P-glycoprotein (P-gp), creating bidirectional interaction potential. It can raise levels of CYP3A4 substrates and its own levels can be altered by CYP3A4 inducers or inhibitors. Additionally, its cardiac conduction effects create pharmacodynamic interactions with other rate-slowing drugs.
Monitoring
- Blood PressureBaseline, each titration, then regularly
RoutineBoth seated and standing; monitor closely during initial titration and when combining with other antihypertensives. Maximum antihypertensive effect typically observed by 14 days. - Heart Rate & ECGBaseline, each titration, periodically
RoutineAssess for bradycardia, PR prolongation, and AV block. ECG essential before initiation to rule out pre-existing conduction abnormalities. Mandatory continuous monitoring during IV administration. - Liver Function TestsBaseline, then as indicated
Trigger-basedAcute hepatic injury reported within 1–8 weeks of initiation; usually reversible upon discontinuation. Check LFTs if jaundice, dark urine, or unexplained fatigue develops. - Peripheral EdemaEach visit
RoutineDose-dependent; differentiate from heart failure. Consider adding ACE-I/ARB or dose reduction before discontinuing diltiazem. - Cyclosporine LevelsAt initiation and dose changes
Trigger-basedIn transplant recipients; 15–48% cyclosporine dose reduction typically needed. Monitor when starting, adjusting, or stopping diltiazem. - Digoxin LevelsAt initiation and dose changes
Trigger-basedDigoxin levels may increase ~20% with concurrent diltiazem; additive AV nodal effects also a concern.
Contraindications & Cautions
Absolute Contraindications
- Sick sinus syndrome without a functioning ventricular pacemaker
- Second- or third-degree AV block without a functioning ventricular pacemaker
- Hypotension (systolic BP <90 mmHg)
- Hypersensitivity to diltiazem
- Acute MI with pulmonary congestion documented on imaging
- Concurrent IV beta-blocker (for IV diltiazem only) — risk of severe bradycardia, AV block, and asystole
Relative Contraindications (Specialist Input Recommended)
- Heart failure with reduced ejection fraction — negative inotropy may worsen ventricular dysfunction; limited safety data in this population
- Wide-complex tachycardia of uncertain origin — if the rhythm is ventricular tachycardia, AV nodal blockade can cause hemodynamic collapse
- Wolff-Parkinson-White (WPW) syndrome with atrial fibrillation — may accelerate conduction down the accessory pathway, potentially triggering ventricular fibrillation
- Moderate to severe hepatic impairment — AUC increased 69% in cirrhosis; requires close dose supervision
Use with Caution
- Concurrent digoxin or beta-blocker therapy — additive effects on cardiac conduction; careful titration required
- Concurrent CYP3A4-metabolized statins — simvastatin must be limited to 10 mg/day; consider pravastatin or rosuvastatin
- Elderly patients — increased sensitivity to bradycardia and conduction disturbances
- Planned surgery with high-dose fentanyl anesthesia — additive depression of cardiac contractility and conduction
Diltiazem prolongs AV nodal refractoriness and can cause second- or third-degree AV block (0.40% in clinical trials). A case of asystole lasting 2–5 seconds was reported in a patient with Prinzmetal angina after a single 60 mg dose. Patients with sick sinus syndrome are at increased risk. Concomitant use with beta-blockers or digoxin may produce additive effects on cardiac conduction. ECG monitoring is mandatory during IV administration and strongly recommended at baseline and during oral titration. Diltiazem should only be used in patients with second- or third-degree AV block or sick sinus syndrome if a functioning ventricular pacemaker is in place.
Patient Counselling
Purpose of Therapy
Diltiazem is prescribed to lower blood pressure, prevent chest pain (angina), or control heart rate in certain heart rhythm disorders. It works by relaxing blood vessels and slowing the heart’s electrical conduction. For blood pressure and angina, long-term daily use provides continuous protection. This medication does not stop chest pain once it has started — short-acting nitroglycerin should be used for acute episodes.
How to Take
Swallow extended-release capsules or tablets whole; never crush, chew, or split them, as this destroys the controlled-release mechanism and may cause a dangerous sudden release of the medication. Immediate-release tablets should be taken before meals and at bedtime. Take at the same time each day for consistent blood levels. Avoid grapefruit juice, which can increase diltiazem levels. Avoid alcohol with Cardizem CD formulation, as it increases the rate of drug release.
Sources
- Cardizem (diltiazem hydrochloride) Tablets. Full Prescribing Information. Bausch Health US, LLC. Revised 2014. accessdata.fda.gov FDA label for the immediate-release tablet formulation; source of IR dosing, adverse effect incidence (angina trials), drug interactions, and PK data.
- Cardizem CD (diltiazem HCl) Extended-Release Capsules. Full Prescribing Information. Bausch Health US, LLC. Revised 2025. accessdata.fda.gov FDA label for the CD once-daily capsule; source of ER dosing for hypertension and angina, PK profile, alcohol interaction, and simvastatin dose limits.
- Cardizem LA (diltiazem HCl) Extended-Release Tablets. Full Prescribing Information. Bausch Health US, LLC. Revised April 2025. accessdata.fda.gov Most recently updated FDA label; source of Cardizem LA-specific dosing, angina study adverse effects, and updated contraindication list including WPW.
- Gibson RS, Boden WE, Theroux P, et al. Diltiazem and reinfarction in patients with non-Q-wave myocardial infarction: results of a double-blind, randomized, multicenter trial. N Engl J Med. 1986;315(7):423-429. doi:10.1056/NEJM198608143150703 Multicenter RCT showing diltiazem reduced reinfarction and refractory angina in non-Q-wave MI patients, establishing its role in selected post-MI settings.
- The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med. 1988;319(7):385-392. doi:10.1056/NEJM198808183190701 Landmark trial showing that diltiazem had no overall benefit in post-MI patients but was associated with increased heart failure events in patients with reduced ejection fraction.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. Hypertension. 2018;71(6):e13-e115. doi:10.1161/HYP.0000000000000065 Current US hypertension guideline; non-dihydropyridine CCBs are second-line options for hypertension but first-line for concurrent rate control needs.
- January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 guideline for management of patients with atrial fibrillation. Circulation. 2019;140(2):e125-e151. doi:10.1161/CIR.0000000000000665 AHA/ACC/HRS guideline recommending diltiazem as a first-line rate-control agent for atrial fibrillation in patients without HFrEF.
- Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease. J Am Coll Cardiol. 2012;60(24):e44-e164. doi:10.1016/j.jacc.2012.07.013 ACCF/AHA guideline for stable angina positioning non-dihydropyridine CCBs as alternatives to beta-blockers when heart rate reduction is a therapeutic goal.
- Hockerman GH, Peterson BZ, Johnson BD, Catterall WA. Molecular determinants of drug binding and action on L-type calcium channels. Annu Rev Pharmacol Toxicol. 1997;37:361-396. doi:10.1146/annurev.pharmtox.37.1.361 Definitive review of L-type calcium channel binding pharmacology explaining diltiazem’s benzothiazepine binding site and its distinct profile from dihydropyridines and phenylalkylamines.
- Godfraind T. Discovery and development of calcium channel blockers. Front Pharmacol. 2017;8:286. doi:10.3389/fphar.2017.00286 Comprehensive review of CCB pharmacology placing diltiazem’s unique profile between dihydropyridines and verapamil in terms of cardiac vs. vascular selectivity.
- Talreja O, Cassagnol M. Diltiazem. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026. Updated August 28, 2023. ncbi.nlm.nih.gov Comprehensive overview including dosing by formulation, PK data, adverse effects, drug interactions, and monitoring parameters across clinical settings.
- Abernethy DR, Schwartz JB, Todd EL, Luchi R, Snow E. Verapamil pharmacodynamics and disposition in young and elderly hypertensive patients: altered electrocardiographic and hypotensive responses. Ann Intern Med. 1986;105(3):329-336. doi:10.7326/0003-4819-105-3-329 Pharmacokinetic study in elderly patients applicable to non-dihydropyridine CCBs as a class, demonstrating increased sensitivity to cardiac effects in older adults.
- Diltiazem. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): NIDDK; 2012. Updated 2020. ncbi.nlm.nih.gov NIH resource documenting diltiazem-associated hepatotoxicity patterns, onset timing (1–8 weeks), and reversibility upon discontinuation.