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Diltiazem Hydrochloride

Class: Calcium-Channel Blocking Agents, Miscellaneous
- Calcium-Channel Blocking Agents, Nondihydropyridine
- Nondihydropyridine Calcium-Channel Blocking Agents
- Calcium Antagonists
VA Class: CV200
CAS Number: 33286-22-5
Brands: Cardizem, Cartia XT, Dilt XR, Matzim LA, Taztia XT, Tiazac

Medically reviewed by Drugs.com. Last updated on Nov 5, 2018.

Introduction

Calcium-channel blocking agent; nondihydropyridine derivative.a

Uses for Diltiazem Hydrochloride

Angina

Management of Prinzmetal variant angina and chronic stable angina1100 1101

A drug of choice for the management of Prinzmetal variant angina (used alone or in combination with nitrates).1100

β-Blockers are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina; calcium-channel blockers may be substituted or added in patients who do not tolerate or respond adequately to β-blockers.1101

Also may be beneficial in patients with unstable angina; experts recommend a nondihydropyridine calcium-channel blocker (e.g., diltiazem, verapamil) for the relief of ongoing or recurrent ischemia when β-blocker therapy is inadequate, not tolerated, or contraindicated in patients with unstable angina who do not have clinically important left ventricular dysfunction, increased risk of cardiogenic shock, or AV block.1100

Hypertension

Oral management of hypertension (alone or in combination with other classes of antihypertensive agents).138 187 188 189 190 272 1200

Calcium-channel blockers are recommended as one of several preferred agents for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics.501 502 503 504 1200 While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 503 504 1200 1213

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).502 503 504 515 1200 1201

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.1200 (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

Table 1. ACC/AHA BP Classification in Adults1200

Category

SBP (mm Hg)

DBP (mm Hg)

Normal

<120

and

<80

Elevated

120–129

and

<80

Hypertension, Stage 1

130–139

or

80–89

Hypertension, Stage 2

≥140

or

≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.1200 However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.501 503 504 505 506 507 508 515 523 526 530 1200 1201 1207 1209 1222 1223 1229

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200 In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.1200 These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.1200 1202 1210

Previous hypertension guidelines generally have based target BP goals on age and comorbidities.501 504 536 Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk, and have used higher BP thresholds and target BPs in elderly patients501 504 compared with those recommended by the 2017 ACC/AHA hypertension guideline.1200

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.1222 1223 1224 1229

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient’s BP treatment goal.1200 1220 1229

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.1200 1207 ASCVD risk assessment recommended by ACC/AHA for all adults with hypertension.1200

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).1200

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.1200

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years of age are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.1200

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.1200 Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in patients with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.1200

Calcium-channel blockers may be preferred in hypertensive patients with certain coexisting conditions (e.g., ischemic heart disease)146 148 159 160 169 523 and in geriatric patients, including those with isolated systolic hypertension.147 153 154 166 167 170 171 502 510 Nondihydropyridine calcium-channel blockers (e.g., diltiazem, verapamil) may be beneficial in hypertensive patients with coexisting atrial fibrillation and a rapid ventricular rate.502 504

Black hypertensive patients generally respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).1200 501 504 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.1200

Only extended-release formulations of diltiazem currently are recommended for management of hypertension.1200

Supraventricular Arrhythmias

Management of supraventricular tachycardias (SVTs), including rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias (PSVT) (e.g., those associated with Wolff-Parkinson-White or Lown-Ganong-Levine syndrome), and control of rapid ventricular rate in atrial flutter or fibrillation.237 238 239 244 245 247 250 252 253 256 257 258 262 700 701

Vagal maneuvers and/or IV adenosine are considered first-line interventions for acute treatment of SVT when clinically indicated; if such measures are ineffective or not feasible, a nondihydropyridine calcium-channel blocker such as diltiazem may be used.700 Use only in hemodynamically stable patients who do not have impaired ventricular function.700

Also has been used for treatment of other SVTs (e.g., atrial tachycardia, junctional tachycardia).700

Acute MI

Used in the early treatment and secondary prevention of acute MI; an effective anti-ischemic agent, but mortality benefit not demonstrated.266 527 1100

Calcium-channel blockers generally are used for their anti-ischemic and BP-reducing properties in the MI setting, and only when β-blockers (which have been shown to reduce mortality after MI) are ineffective, not tolerated, or contraindicated.527 702 1100

Experts state that calcium-channel blockers may be used to relieve ischemic symptoms, lower BP, or control rapid ventricular response rate associated with atrial fibrillation in patients with ST-segment-elevation MI (STEMI) who are intolerant to β-blockers.527

Experts recommend a nondihydropyridine calcium-channel blocker for ongoing or recurrent ischemia in patients with non-ST-segment-elevation MI (NSTEMI) who have a contraindication to β-blockers and who do not have clinically important left ventricular dysfunction, increased risk of cardiogenic shock, or AV block.1100

Hyperthyroidism

Short-term adjunctive therapy in the treatment of tachycardia and tachyarrhythmias in patients with hyperthyroidism and/or thyrotoxicosis in whom therapy with β-adrenergic blocking agents is contraindicated or not tolerated.172 173 174

Diltiazem Hydrochloride Dosage and Administration

General

BP Monitoring and Treatment Goals

  • Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.1200

  • If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.1200 1216

  • If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, thiazide diuretic).1200 1216 Many patients will require at least 2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved with 2 antihypertensive agents, add a third drug.1200 1216

Administration

Administer by direct IV injection, continuous IV infusion, or orally.138 187 190 237 323 600

Oral Administration

Conventional Tablets

Administer tablets orally 3–4 times daily before meals and at bedtime.100

Extended-release Capsules

Administer orally; directions for administration (e.g., dosing frequency, whether to administer with or without food, potential for opening capsules and mixing with food) may vary by manufacturer and formulation; consult specific manufacturer’s information for additional information.

Cardizem CD, Dilt-XR, Tiazac, Taztia XT, or Cartia XT may be administered once daily;187 324 325 326 some diltiazem hydrochloride extended-release capsules (12 hours) are administered twice daily.b

Cardizem CD and Cartia XT may be administered without regard to meals.188 325 However, Dilt-XR should be taken on an empty stomach, swallowed whole and not opened, chewed, or crushed.324

Tiazac and Taztia XT may be opened and the entire contents sprinkled on a small amount of applesauce (not hot) immediately prior to administration; subdividing the contents of capsules is not recommended.305 326 Swallow the entire mixture without chewing.305 326 Immediately drink a glass of cool water to ensure that all of the mixture is swallowed.305 326 Do not store the sprinkle/food mixture for use at a later time.305 326

Extended-release Tablets

Administer orally once daily without regard to meals.323 600 Tablet should be swallowed whole and not chewed or crushed.323 600

IV Injection

For solution and drug compatibility information, see Compatibility under Stability.

Monitor ECG and BP continuously during IV administration.237

Dilution

Injection solutions containing 5 mg/mL may be administered by direct IV injection without any further dilution.237

Rate of Administration

Administer over 2 minutes.237

IV Infusion

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Prepare 1-mg/mL solutions from the powder for IV infusion in ADD-Vantage vials according to the manufacturer’s directions.332

Dilution

Alternatively, dilute 5-mg/mL injection solution in the appropriate volume of a compatible infusion solution (i.e., 0.9% sodium chloride, 5% dextrose, or 5% dextrose and 0.45% sodium chloride) to produce a final diltiazem hydrochloride concentration of 1, 0.83, or 0.45 mg/mL, respectively.237

Dilution of Commercially Available Injection.237

Quantity of 5 mg/mL Solution

Diluent Volume

Final Concentration

25 mL

100 mL

1 mg/mL

50 mL

250 mL

0.83 mg/mL

50 mL

500 mL

0.45 mg/mL

Rate of Administration

Usually 10 mg/hour; however, may range from 5–15 mg/hour.237

Dosage

Available as diltiazem hydrochloride; dosage expressed in terms of the salt.179 236 237

Adults

Prinzmetal Variant Angina
Conventional Tablets
Oral

Initially, 30 mg 4 times daily.100 Increase gradually at 1- to 2-day intervals until optimum control is obtained. Usual maintenance dosage is 180–360 mg daily.100 After manifestations are controlled, reduce dosage to lowest level that will maintain relief of symptoms.a

Extended-release Capsules
Oral

Initially, 120 or 180 mg once daily when administered as extended-release capsules (Cardizem CD, Cartia XT).187 325 Individualize dosage based on response; titrate dosage increases over 7–14 days.187 325 Some patients may respond to higher dosages of up to 480 mg once daily.187 325

Chronic Stable Angina
Conventional Tablets
Oral

Initially, 30 mg 4 times daily.100 Increase gradually at 1- to 2-day intervals until optimum control is obtained. Usual maintenance dosage is 180–360 mg daily.100 After manifestations are controlled, reduce dosage to lowest level that will maintain relief of symptoms.a

Extended-release Capsules
Oral

Initially, 120 mg (Dilt-XR) or 120–180 mg (Cardizem CD, Cartia XT, Tiazac, Taztia XT) once daily when administered as extended-release capsules.187 274 324 325 326 Individualize dosage based on response; titrate dosage increases over 7–14 days.187 274 324 325 326 Some patients may respond to higher dosages of up to 480 (Cardizem CD, Cartia XT, Dilt-XR) to 540 mg (Tiazac, Taztia XT) once daily.187 274 324 325 326

Extended-release Tablets
Oral

Initially, 180 mg once daily when administered as extended-release tablets (Cardizem LA or Matzim LA).323 600 Individualize dosage based on response; titrate dosage increases over 7–14 days.323 600 Some patients may respond to higher dosages of up to 360 mg once daily.323

Hypertension
Extended-release Capsules or Tablets
Oral

Manufacturer-recommended dosages vary based on formulation (see Table 2).

Per some experts, usual maintenance dosage of extended-release diltiazem hydrochloride for management of hypertension is 120–360 mg once daily.1200

Maximum hypotensive effect associated with a given dosage level usually is observed within 14 days.138 187 274 275 323 325 326

Table 2. Manufacturer-recommended Dosages for Management of Hypertension

Preparation

Initial Dosage

Usual Maintenance Dosage

Cardizem LA

180–240 mg once daily323

120–540 mg;323

Cardizem CD

180–240 mg once daily187

240–360 mg daily187

Cartia XT

180–240 mg once daily325

240–360 mg daily325

Diltiazem hydrochloride extended-release capsules (12 hours)

60–120 mg twice dailyb

240–360 mg dailyb

Dilt-XR

180–240 mg once daily324

180–480 mg once daily324

Matzim LA

180–240 mg once daily600

Tiazac

120–240 mg once daily274

120–540 mg once daily274

Taztia XT

120–240 mg once daily326

120–540 mg once daily326

Switching to Extended-release Preparations
Oral

Patients whose BP is adequately controlled with diltiazem therapy (as tablets or other extended-release capsules) alone or in combination with another antihypertensive agent may be safely switched to Cardizem CD or Cartia XT extended-release capsules or Cardizem LA or Matzim LA extended-release tablets at the nearest equivalent daily dosage.187 323 325 600 Subsequent titration of dosage is based on the clinical response of the patient.187 323 325 600

Supraventricular Arrhythmias
Conversion of PSVT to Sinus Rhythm
IV

Initially, 0.25 mg/kg based on actual body weight (average dose: 20 mg) by direct IV injection over 2 minutes.256 703 If response is inadequate (i.e., conversion to normal sinus rhythm does not occur) give a second dose of 0.35 mg/kg based on actual body weight (average dose: 25 mg) 15 minutes after the initial dose.257 703

Maintenance infusion: 5–15 mg/hour; titrate dose to heart rate.293 703

Patients with low body weights should be dosed on a mg/kg basis.703

Ventricular Rate Control in Atrial Fibrillation and Flutter
IV

Initially, 0.25 mg/kg based on actual body weight (average dose: 20 mg) by direct IV injection over 2 minutes.703 If response is inadequate, give 0.35 mg/kg based on actual body weight (average dose: 25 mg) 15 minutes after the initial dose.246 703

Maintenance infusion: 5–15 mg/hour; titrate dose to heart rate.700 703

Other SVTs (e.g., Junctional Tachycardia, Atrial Tachycardia)
IV

Initially, 0.25 mg/kg by direct IV injection over 2 minutes followed by a maintenance IV infusion of 5–10 mg/hour (up to 15 mg/hour).700

Prescribing Limits

Adults

Angina
Oral

Cardizem LA and Matzim LA extended-release tablets: Maximum 360 mg daily.323 600

Cardizem CD, Dilt-XR, and Cartia XT extended-release capsules: Maximum 480 mg daily.187 324 325

Tiazac and Taztia XT extended-release capsules: Maximum 540 mg daily.274 326

Hypertension
Oral

Cardizem CD and Cartia XT extended-release capsules: Maximum 480 mg daily.187 325

Dilt-XR,Taztia XT, and Tiazac extended-release capsules and Cardizem LA and Matzim LA extended-release tablets: Maximum 540 mg daily.274 323 324 326 600

Supraventricular Arrhythmias
IV

Maintenance infusion: Maximum 15 mg/hour for ≤24 hours.244 293

Special Populations

Hepatic Impairment

Supraventricular Arrhythmias
Atrial Fibrillation and Flutter
IV

Maintenance infusion: Dosage requirements may be lower.245 703

Geriatric Patients

Angina

Select dosage cautiously; geriatric patients may respond to lower dosages.100 138 187 274 323 326 a

Hypertension

Select dosage cautiously.138 187 274 323 326 The manufacturer of Dilt-XR states that patients ≥60 years of age may respond to an initial daily dosage of 120 mg.324

Atrial Fibrillation and Flutter

Maintenance IV infusion: Dosage requirements may be lower.237 245

Cautions for Diltiazem Hydrochloride

Contraindications

  • Contraindicated in patients with known hypersensitivity to the drug.237 252 253 256 258

  • Sick sinus syndrome (unless a functioning ventricular pacemaker is in place).237 252 253 256 258

  • Second- or third-degree AV block (unless a functioning ventricular pacemaker is in place).237 252 253 256 258

  • Severe hypotension (SBP <90 mm Hg).237 252 253 256 258

  • Oral preparations contraindicated in patients with acute MI with radiographically documented pulmonary congestion.138 187 190 200 237

  • IV diltiazem contraindicated in patients with cardiogenic shock.237 252 253 256 258

  • IV diltiazem contraindicated in patients with VT.237 257

  • IV diltiazem contraindicated in patients with atrial flutter or fibrillation with an accessory pathway (e.g., those with Wolff-Parkinson-White or Lown-Ganong-Levine syndrome).237 262

  • IV diltiazem contraindicated if concurrent or recent (e.g., within a few hours) administration of IV β-adrenergic blockers.237

Warnings/Precautions

Warnings

Cardiac Conduction

Potential for abnormally slow heart rate (particularly in patients with sick sinus syndrome) or second- or third-degree AV block.100 138 187 237 274 323

Additive effects on cardiac conduction (e.g., prolonging AV node conduction) possible with concomitant use of diltiazem with β-adrenergic blocking agents or digoxin.100 138 187 237 274 323

If high-degree AV block occurs in patients with sinus rhythm receiving IV diltiazem, discontinue the drug and institute appropriate supportive measures.237

Heart Failure

Risk of heart failure, especially in those with preexisting ventricular impairment; limited experience in patients with impaired ventricular function receiving concomitant β-adrenergic blocking agents.100 138 187 237 251 254 256 258 274 323 Use with caution.100 138 187 274 323

Hypotension

Possible symptomatic hypotension.100 138 187 237 274 323

Acute Hepatic Injury

Substantial elevations in hepatic function test results (e.g., serum AST [SGOT], ALT [SGPT], LDH, alkaline phosphatase) and phenomena associated with hepatocellular injury rarely reported.100 138 187 237 274 323 Usually occurs early in therapy (e.g., 1–8 weeks); reversible upon discontinuation of therapy.100 138 187 237 274 323

Ventricular Premature Beats

With IV administration, possible transient VPB on conversion of PSVT to sinus rhythm;237 appear to be benign and of little clinical importance.237 250

Sensitivity Reactions

Possible diltiazem-induced skin eruptions with oral preparations; may infrequently progress to severe dermatologic reactions (e.g., erythema multiforme, exfoliative dermatitis).100 138 237 If effects persist during therapy, the drug should be discontinued.100 138 237 Potential for occurrence with IV administration.237

Specific Populations

Pregnancy

Category C.100 138 187 190 274 278 323 324 325 326

Lactation

Distributed into milk;100 101 138 187 190 274 278 323 324 325 326 discontinue nursing.100 138 187 190 274 278 323 324 325 326

Pediatric Use

Safety and efficacy not established.100 138 187 190 274 278 323 324 325 326

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.100 138 187 274 323 326 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.100 138 187 274 323 326

Hepatic Impairment

Use with caution.100 138 187 237 274 323

Renal Impairment

Use with caution.100 138 187 237 274 323

Common Adverse Effects

With oral therapy, edema, headache, dizziness, asthenia, first-degree AV block.138 187 274 323

With IV therapy, hypotension, injection site reactions, vasodilation, arrhythmia.237

Interactions for Diltiazem Hydrochloride

Metabolized principally by CYP3A4.100 138 187 274 Inhibits CYP3A4.274

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors, inducers, and substrates of CYP3A4: potential pharmacokinetic interaction (altered plasma diltiazem concentrations).100 138 187 274 323

Drugs Metabolized by Microsomal Enzymes

Potential pharmacokinetic interaction: altered bioavailability and/or clearance of drugs metabolized by CYP3A4.100 116 132 133 138 187 274

Specific Drugs

Drug

Interaction

Comments

Anesthetics, general

Possible increased depression of cardiac contractility, conductivity, and automaticity as well as vascular dilation100 138 187 237 274 323

Titrate dosage of each drug carefully100 138 187 237 274 323

Atazanavir

Possible increased plasma diltiazem concentrations and additive effect on PR interval prolongation318

Use concomitantly with caution.318 Reduce diltiazem dosage by 50%; monitor ECG318

β-Adrenergic blockers

Potential for additive negative effects on myocardial contractility, heart rate, and prolonging AV conduction100 138 187 190 237 263 264 274 295 323

Increased plasma concentrations of propranolol and metoprolol295 296

Do not administer IV diltiazem and IV β-adrenergic blocking agents within a few hours of each other237

Propranolol dosage adjustment may be necessary when diltiazem is initiated or discontinued100

Benzodiazepines (e.g., midazolam, triazolam)

Possible increased benzodiazepine plasma concentrations and AUC resulting in increased adverse effects (e.g., prolonged sedation, respiratory depression)100 138 187 274 299 300 323

Buspirone

Increased plasma concentration and AUC of buspirone100 138 187

Potential for increased effects and toxicity of buspirone100 138 187

Dosage adjustment of buspirone may be necessary based on clinical assessments100 138 187

Carbamazepine

Possible increased serum or plasma carbamazepine concentrations and associated neurologic and sensory manifestations of carbamazepine toxicity138 200 201 202 203 204 205 206 207 208

Avoid concurrent use, if possible203

Monitor for manifestations of carbamazepine toxicity; adjust carbamazepine dosage accordingly138 200 201 202 203 204 205 206 207 208

Clonidine

Sinus bradycardia resulting in hospitalization and pacemaker insertion reported600

Monitor heart rate600

Cyclosporine

Possible increased blood cyclosporine concentrations112 113 237 297 298 and consequent nephrotoxicity112 297 298

Monitor cyclosporine concentration in biologic fluid (especially when diltiazem therapy is initiated, adjusted, or discontinued); adjust cyclosporine dosage as needed100 138 187 237 274 275 276 291 292 297 298

Digoxin

Possible increased serum digoxin concentrations102 105 107 108

Potential for additive effects on cardiac conduction (e.g., prolonging AV node conduction)100 138 187 237 274 323

Monitor serum digoxin concentrations carefully and observe the patient closely for signs of digoxin toxicity when administered concomitantly, especially in geriatric patients, patients with unstable renal function, or those with serum digoxin concentrations in the upper therapeutic range before diltiazem is administered103 105 107 108 111

Reduce digoxin dosage if necessary103 105 107 108 111

Histamine H2-receptor antagonists (e.g., cimetidine, ranitidine)

Possible increased plasma diltiazem concentrations with concomitant administration of cimetidine100 125 126 127

Ranitidine coadministration produced smaller and not substantial alterations in diltiazem pharmacokinetics100 125 126 127

Monitor effects of diltiazem carefully when cimetidine therapy is initiated or discontinued in patients receiving diltiazem; adjust diltiazem dosage, if necessary100 126 127

HMG-CoA reductase inhibitors (e.g., lovastatin, pravastatin, simvastatin)

Possible increased mean AUCs and peak plasma concentrations of lovastatin with concomitant use274 302 600

Increased mean AUCs of simvastatin with concomitant use600 601

May increase risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4600

Interaction not observed when used concomitantly with pravastatin274 302 600

When concomitant use of diltiazem and lovastatin is required, initiate lovastatin at dosage of 10 mg once daily; may increase lovastatin dosage to maximum of 20 mg once daily602

Do not exceed simvastatin dosage of 10 mg daily and diltiazem dosage of 240 mg daily if used concomitantly600 601

Non-CYP3A4-metabolized statin should be used if possible600

Monitor patients receiving lovastatin or simvastatin concomitantly with diltiazem for evidence of statin toxicity (e.g., rhabdomyolysis, myositis)600

Ivabradine

Increased exposure to ivabradine; may exacerbate bradycardia and conduction disturbances600

Avoid concomitant use600

Nitrates

Interaction unlikely100 187

Quinidine

Possible increased AUC and decreased clearance of quinidine100 138 187

Monitor for adverse effects of quinidine; adjust dosage accordingly100 138 187

Rifampin

Decreased bioavailability and increased clearance of diltiazem304

Avoid concomitant use; consider alternative therapy100 138 187 274 304

Diltiazem Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Following oral administration of conventional tablets, approximately 80% of a dose is rapidly absorbed from the GI tract.a

Absolute bioavailability is about 40%; undergoes extensive first-pass metabolism.100 138 187 274 323

Time to Peak Serum Concentrations Following Administration

Preparation

Time (hours)

Conventional tablets (e.g., Cardizem)

2–4100

Cardizem CD extended-release capsules

10–14187

Cardizem LA or Matzim LA extended-release tablets

11–18323 600

Diltiazem hydrochloride extended-release capsules (12 hours)

6–11b

Onset

Following direct IV injection, reductions in heart rate usually occur within 3 minutes237 247 252 and hemodynamic effects (e.g., decrease in BP) generally occur within 2 minutes;237 246 247 252 effects on the AV node generally occur within minutes following initiation of a continuous IV infusion.237 242

Duration

Following direct IV injection, reductions in heart rate generally persist for 1–3 hours;237 247 252 blood pressure reductions following direct IV injection generally are short-lived but may last 1–3 hours.237 Effects on the AV node may persist for 0.5–10 hours following a continuous IV infusion.237 242

Food

Rate of absorption may be increased if Tiazac extended-release capsules are taken with a high-fat meal.274 Food may affect the extent of absorption of some extended-release capsules (Dilt-XR).601

Distribution

Extent

Rapidly and extensively distributed into body tissues.191 245 259

Distributed into milk, in concentrations approximately equal to maternal serum concentrations.100 101 237

Plasma Protein Binding

About 70–85% is bound to plasma proteins, but only 30–40% is bound to albumin.135 237 259

Elimination

Metabolism

Rapidly and almost completely metabolized in the liver to several active and at least 5 inactive metabolites principally via CYP enzyme system, mainly CYP3A4.100 132 134 135 136 137 182 183 237 241 242

Elimination Route

Excreted principally in urine as metabolites,a with approximately 2–4% of a dose excreted unchanged.135 237 259

Half-life

2–11 hours.191 237

Special Populations

In geriatric patients, plasma half-life of the drug may be increased.191 237 239

In patients with severe renal impairment, pharmacokinetics were unchanged.323

Oral clearance may be reduced and half-life prolonged in patients with liver cirrhosis.237

Stability

Storage

Oral

Conventional Tablets

Tight containers at 25°C (may be exposed to 15–30°C).100 a

Protect from excessive humidity.100

Extended-release Capsules

25°C (may be exposed to 15–30°C).138 187 274

Protect from excessive humidity.138 187 274 325 326

Extended-release Tablets

Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).323

Protect from excessive humidity.323

Parenteral

Injection

2–8°C.237 Do not freeze.237 May store at room temperature for up to 1 month; discard after 1 month if not used.237

Diluted solutions (up to 1 mg/mL in 0.9% sodium chloride, 5% dextrose, or 5% dextrose and 0.45% sodium chloride injection) prepared in glass or PVC bags: Store at room temperature or under refrigeration and use within 24 hours.237

Powder for IV Infusion

20–25°C.332 Do not freeze.332

Reconstituted and activated ADD-Vantage vials prepared using 0.9% sodium chloride or 5% dextrose injection: Store at room temperature or under refrigeration and use within 24 hours.332

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Y-site CompatibilityHID

Compatible

Albumin human

Alcohol 10% in dextrose 5%

Amikacin sulfate

Amphotericin B

Argatroban

Aztreonam

Bivalirudin

Bretylium tosylate

Bumetanide

Cefazolin sodium

Cefotaxime sodium

Cefoxitin sodium

Ceftazidime

Ceftriaxone sodium

Cefuroxime sodium

Cimetidine HCl

Ciprofloxacin

Clindamycin phosphate

Co-trimoxazole

Dexmedetomidine HCl

Digoxin

Dobutamine HCl

Dopamine HCl

Doxycycline hyclate

Epinephrine HCl

Erythromycin lactobionate

Esmolol HCl

Fenoldopam mesylate

Fentanyl citrate

Fluconazole

Gentamicin sulfate

Hetastarch in lactated electrolyte injection (Hextend)

Hetastarch in sodium chloride 0.9%

Hydromorphone HCl

Imipenem–cilastatin sodium

Labetalol HCl

Lidocaine HCl

Lorazepam

Meperidine HCl

Metoclopramide HCl

Metronidazole

Metronidazole HCl

Midazolam HCl

Milrinone lactate

Morphine sulfate

Multivitamins (M.V.I.-12)

Nicardipine HCl

Nitroglycerin

Norepinephrine bitartrate

Oxacillin sodium

Penicillin G potassium

Pentamidine isethionate

Potassium chloride

Potassium phosphates

Ranitidine HCl

Sodium nitroprusside

Theophylline

Ticarcillin disodium–clavulanate potassium

Tobramycin sulfate

Vancomycin HCl

Vasopressin

Vecuronium bromide

Incompatible

Diazepam

Furosemide

Lansoprazole

Phenytoin sodium

Rifampin

Thiopental sodium

Variable

Acetazolamide sodium

Acyclovir sodium

Aminophylline

Ampicillin sodium

Ampicillin sodium–sulbactam sodium

Heparin sodium

Hydrocortisone sodium succinate

Methylprednisolone sodium succinate

Nafcillin sodium

Procainamide HCl

Sodium bicarbonate

Actions

  • Inhibits transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium concentrations.100 138 187 274 323

  • Peripheral arterial vasodilator; acts directly on vascular smooth muscle causing reduction in peripheral vascular resistance (afterload) and BP.100 138 187 274 323

  • Substantial inhibitory effects on the cardiac conduction system, acting principally at the atrioventricular (AV) node to slow conduction time and prolong AV nodal refractoriness.237

Advice to Patients

  • Importance of swallowing extended-release tablets whole; do not chew, crush, or break.323

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.100 138 187 274 323

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.100 138 187 274 323

  • Importance of informing patients of other important precautionary information.100 138 187 274 323 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

dilTIAZem Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release

60 mg*

Diltiazem Hydrochloride Capsules Extended-release (12 hours)

90 mg*

Diltiazem Hydrochloride Capsules Extended-release (12 hours)

120 mg*

Cardizem CD (24 hours)

Valeant

Cartia XT (24 hours)

Actavis

Dilt-XR (24 hours)

Apotex

Diltiazem Hydrochloride Capsules Extended-release (12 hours)

Diltiazem Hydrochloride Capsules Extended-release (24 hours)

Taztia XT (24 hours)

Actavis

Tiazac (24 hours)

Valeant

180 mg*

Cardizem CD (24 hours)

Valeant

Cartia XT (24 hours)

Actavis

Dilt-XR (24 hours)

Apotex

Diltiazem Hydrochloride Capsules Extended-release (24 hours)

Taztia XT (24 hours)

Actavis

Tiazac (24 hours)

Valeant

240 mg*

Cardizem CD (24 hours)

Valeant

Cartia XT (24 hours)

Actavis

Dilt-XR (24 hours)

Apotex

Diltiazem Hydrochloride Capsules Extended-release (24 hours)

Taztia XT (24 hours)

Actavis

Tiazac (24 hours)

Valeant

300 mg*

Cardizem CD (24 hours)

Valeant

Cartia XT (24 hours)

Actavis

Dilt XR (24 hours)

Apotex

Diltiazem Hydrochloride Capsules Extended-release (24 hours)

Taztia XT (24 hours)

Actavis

Tiazac (24 hours)

Valeant

360 mg*

CardizemCD (24 hours)

Valeant

Diltiazem Hydrochloride Capsules Extended-release (24 hours)

Taztia XT (24 hours)

Actavis

Tiazac (24 hours)

Valeant

420 mg

Tiazac (24 hours)

Valeant

Tablets

30 mg*

Cardizem

Valeant

Diltiazem Hydrochloride Tablets

60 mg*

Cardizem (scored)

Valeant

Diltiazem Hydrochloride Tablets

90 mg*

Cardizem (scored)

Valeant

Diltiazem Hydrochloride Tablets

120 mg*

Cardizem (scored)

Valeant

Diltiazem Hydrochloride Tablets

Tablets, extended-release

120 mg*

Cardizem LA (24 hours)

Valeant

Diltiazem Hydrochloride Tablets Extended-release (24 hours)

180 mg*

Cardizem LA (24 hours)

Valeant

Diltiazem Hydrochloride Tablets Extended-release (24 hours)

Matzim LA (24 hours)

Actavis

240 mg*

Cardizem LA (24 hours)

Valeant

Diltiazem Hydrochloride Tablets Extended-release (24 hours)

Matzim LA (24 hours)

Actavis

300 mg*

Cardizem LA (24 hours)

Valeant

Diltiazem Hydrochloride Tablets Extended-release (24 hours)

Matzim LA (24 hours)

Actavis

360 mg*

Cardizem LA (24 hours)

Valeant

Diltiazem Hydrochloride Tablets Extended-release (24 hours)

Matzim LA (24 hours)

Actavis

420 mg*

Cardizem LA (24 hours)

Valeant

Diltiazem Hydrochloride Tablets Extended-release (24 hours)

Matzim LA (24 hours)

Actavis

Parenteral

For injection, for IV infusion only

100 mg*

Diltiazem Hydrochloride for Injection ADD-Vantage

Hospira

Injection

5 mg/mL (25, 50, and 125 mg)*

Diltiazem Hydrochloride Injection

AHFS DI Essentials™. © Copyright 2019, Selected Revisions November 5, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Biovail Pharmaceuticals, Inc. Cardizem (diltiazem hydrochloride) direct compression tablets prescribing information. Morrisville, NC; 2001 Aug.

101. Okada M, Inoue H, Nakamura Y et al. Excretion of diltiazem in human milk. N Engl J Med. 1985; 312:992-3. http://www.ncbi.nlm.nih.gov/pubmed/3974691?dopt=AbstractPlus

102. Oyama Y, Fujii S, Kanda K et al. Digoxin-diltiazem interaction. Am J Cardiol. 1984; 53:1480-1. http://www.ncbi.nlm.nih.gov/pubmed/6720603?dopt=AbstractPlus

103. Boden WE, More G, Sharma S et al. No increase in serum digoxin concentration with high-dose diltiazem. Am J Med. 1986; 81:425-8. http://www.ncbi.nlm.nih.gov/pubmed/3752143?dopt=AbstractPlus

104. Yoshida A, Fujita M, Kurosawa N et al. Effects of diltiazem on plasma level and urinary excretion of digoxin in healthy subjects. Clin Pharmacol Ther. 1984; 35:681-5. http://www.ncbi.nlm.nih.gov/pubmed/6713780?dopt=AbstractPlus

105. Rameis H, Magometschnigg D, Ganzinger U. The diltiazem-digoxin interaction. Clin Pharmacol Ther. 1984; 36:183-9. http://www.ncbi.nlm.nih.gov/pubmed/6744777?dopt=AbstractPlus

106. Schrager BR, Pina I, Frangi M et al. Diltiazem, digoxin interaction? Circulation. 1983; 68(Suppl III):III-368. Abstract No. 1471.

107. Kuhlmann J. Effects of nifedipine and diltiazem on plasma levels and renal excretion of beta-acetyldigoxin. Clin Pharmacol Ther. 1985; 37:150-6. http://www.ncbi.nlm.nih.gov/pubmed/3967458?dopt=AbstractPlus

108. North DS, Mattern AL, Hiser WW. The influence of diltiazem hydrochloride on trough serum digoxin concentrations. Drug Intell Clin Pharm. 1986; 20:500-3. http://www.ncbi.nlm.nih.gov/pubmed/3720546?dopt=AbstractPlus

109. Elkayam U, Parikh K, Torkan B et al. Effect of diltiazem on renal clearance and serum concentration of digoxin in patient with cardiac disease. Am J Cardiol. 1985; 55:1393-5. http://www.ncbi.nlm.nih.gov/pubmed/3993576?dopt=AbstractPlus

110. Beltrami T, May JJ, Bertino JS Jr. Lack of effects of diltiazem on digoxin pharmacokinetics. J Clin Pharmacol. 1985; 25:390-2. http://www.ncbi.nlm.nih.gov/pubmed/4031117?dopt=AbstractPlus

111. Hansten PD. Diltiazem and digoxin. Drug Interact Newsl. 1984; 4:33-4.

112. Pochet JM, Pirson Y. Cyclosporin-diltiazem interaction. Lancet. 1986; 1:979. http://www.ncbi.nlm.nih.gov/pubmed/2871278?dopt=AbstractPlus

113. Grino JM, Sabate I, Castelao AM et al. Influence of diltiazem on cyclosporin clearance. Lancet. 1986; 1:1387. http://www.ncbi.nlm.nih.gov/pubmed/2872500?dopt=AbstractPlus

114. Marion Labs Inc. Cardizem tablets (diltiazem hydrochloride) prescribing information. Kansas City, MO; 1982 Nov.

115. McGraw BF, Walker SD, Hemberger JA et al. Clinical experience with diltiazem in Japan. 1982; 2:156-61.

116. Carrum G, Egan JM, Abernethy DR. Diltiazem treatment impairs hepatic drug oxidation: studies of antipyrine. Clin Pharmacol Ther. 1986; 40:140-3. http://www.ncbi.nlm.nih.gov/pubmed/3731677?dopt=AbstractPlus

117. Malcolm N, Callegari P, Goldberg J et al. Massive diltiazem overdosage: clinical and pharmacokinetic observations. Drug Intell Clin Pharm. 1986; 20:888. http://www.ncbi.nlm.nih.gov/pubmed/3780429?dopt=AbstractPlus

118. Jakubowski AT, Mizgala HF. Effect of diltiazem overdose. Am J Cardiol. 1987; 60:932-3. http://www.ncbi.nlm.nih.gov/pubmed/3661417?dopt=AbstractPlus

119. Scolnick B, Brinberg D. Diltiazem and generalized lymphadenopathy. Ann Intern Med. 1985; 102:558. http://www.ncbi.nlm.nih.gov/pubmed/3156549?dopt=AbstractPlus

120. Henry M, Kay MM, Viccellio P. Cardiogenic shock associated with calcium-channel and beta blockers: reversal with intravenous calcium chloride. Am J Emerg Med. 1985; 3:334-6. http://www.ncbi.nlm.nih.gov/pubmed/2860911?dopt=AbstractPlus

121. Moroni F, Mannaioni PF, Dolara A et al. Calcium gluconate and hypertonic sodium chloride in a case of massive verapamil poisoning. Clin Toxicol. 1980; 17:395-400. http://www.ncbi.nlm.nih.gov/pubmed/7449353?dopt=AbstractPlus

122. Perkins CM. Serious verapamil poisoning: treatment with intravenous calcium gluconate. Br Med J. 1978; 2:1127. http://www.ncbi.nlm.nih.gov/pubmed/709264?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1608261&blobtype=pdf

123. Woie L, Storstein L. Successful treatment of suicidal verapamil poisoning with calcium gluconate. Eur Heart J. 1981; 2:239-42. http://www.ncbi.nlm.nih.gov/pubmed/7274286?dopt=AbstractPlus

124. Class IV drugs: calcium channel blockers. In: Ellenhorn MJ, Barceloux DG, eds. Medical toxicology: diagnosis and treatment of human poisoning. New York: Elsevier Science Publishing, Inc; 1988:195-200.

125. Winship LC, McKenney JM, Wright JT et al. The effect of ranitidine and cimetidine on single-dose diltiazem pharmacokinetics. Pharmacotherapy. 1985; 5:16-9. http://www.ncbi.nlm.nih.gov/pubmed/3982974?dopt=AbstractPlus

126. Diltiazem/histamine H2 Antagonists. In: Tatro DS, Olin BR, Hebel SK, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1991 (October):298.

127. Cimetidine (Tagamet) drug interaction: Diltiazem (Cardizem). In: Hansten PD, Horn JR. Drug interactions analysis and management. Vancouver, WA: Applied Therapeutics, Inc; 1997: 141.

128. Strubelt O, Diederich KW. Experimental investigations on the antidotal treatment of nifedipine overdosage. J Toxicol Clin Toxicol. 1986; 24:135-49. http://www.ncbi.nlm.nih.gov/pubmed/3712523?dopt=AbstractPlus

129. Strubelt O. Antidotal treatment of the acute cardiovascular toxicity of verapamil. Acta Pharmacol Toxicol (Copenh). 1984; 55:231-7. http://www.ncbi.nlm.nih.gov/pubmed/6507111?dopt=AbstractPlus

130. Passal DB, Crespin FH Jr. Verapamil poisoning in an infant. Pediatrics. 1984; 73:543-5. http://www.ncbi.nlm.nih.gov/pubmed/6709437?dopt=AbstractPlus

131. Herrington DM, Insley BM, Weinmann GG. Nifedipine overdose. Am J Med. 1986; 81:344-6. http://www.ncbi.nlm.nih.gov/pubmed/3740090?dopt=AbstractPlus

132. Renton KW. Inhibition of hepatic microsomal drug metabolism by the calcium channel blockers diltiazem and verapamil. Biochem Pharmacol. 1985; 34:2549-53. http://www.ncbi.nlm.nih.gov/pubmed/4015695?dopt=AbstractPlus

133. Bauer LA, Stenwall M, Horn JR et al. Changes in antipyrine and indocyanine green kinetics during nifedipine, verapamil, and diltiazem therapy. Clin Pharmacol Ther. 1986; 40:239-42. http://www.ncbi.nlm.nih.gov/pubmed/3731687?dopt=AbstractPlus

134. Sugihara J, Sugawara Y, Ando H et al. Studies on the metabolism of diltiazem in man. J Pharmacobio Dyn. 1984; 7:24-32. http://www.ncbi.nlm.nih.gov/pubmed/6726609?dopt=AbstractPlus

135. Echizen H, Eichelbaum M. Clinical pharmacokinetics of verapamil, nifedipine and diltiazem. Clin Pharmacokinet. 1986; 22:425-49.

136. Rovei V, Gomeni R, Mitchard M et al. Pharmacokinetics and metabolism of diltiazem in man. Acta Cardiol. 1980; 35:35-45. http://www.ncbi.nlm.nih.gov/pubmed/6967667?dopt=AbstractPlus

137. Clozel JP, Caillé G, Taeymans Y et al. High-performance liquid chromatographic determination of diltiazem and six of its metabolites in human urine. J Pharm Sci. 1984; 73:771-3. http://www.ncbi.nlm.nih.gov/pubmed/6737261?dopt=AbstractPlus

138. Biovail Pharmaceuticals, Inc. Cardizem SR (diltiazem hydrochloride) sustained-release capsules prescribing information. Morrisville, NC; 2001 Aug.

141. The Expert Panel (coordinated by the National Heart, Lung, and Blood Institute). Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med. 1988; 148:36-69. http://www.ncbi.nlm.nih.gov/pubmed/3422148?dopt=AbstractPlus

142. Andrén L, Höglund P, Dotevall A et al. Diltiazem in hypertensive patients with type II diabetes mellitus. Am J Cardiol. 1988; 62:114-20G.

143. Pool PE, Massie BM, Venkataraman K et al. Diltiazem as monotherapy for systemic hypertension: a multicenter, randomized, placebo-controlled trial. Am J Cardiol. 1986; 57:212-7. http://www.ncbi.nlm.nih.gov/pubmed/3511660?dopt=AbstractPlus

144. Pool PE, Seagren SC, Salel AF et al. Effects of diltiazem on serum lipids, exercise performance and blood pressure: randomized, double-blind, placebo-controlled evaluation for systemic hypertension. Am J Cardiol. 1985; 56:86-91H.

145. Wolfson P, Abernethy D, DiPette DJ et al. Diltiazem and captopril alone or in combination for the treatment of mild to moderate systemic hypertension. Am J Cardiol. 1988; 62:103-8G.

146. Kawanishi DT, Leman RB, Pratt CM et al. Efficacy and safety of sustained-release diltiazem as replacement therapy for beta blockers and diuretics for stable angina pectoris and coexisting essential hypertension: a multicenter trial. Am J Cardiol. 1987; 60:29-35I.

147. Massie B, MacCarthy EP, Ramanathan KB et al. Diltiazem and propranolol in mild to moderate essential hypertension as monotherapy or with hydrochlorothiazide. Ann Intern Med. 1987; 107:150-7. http://www.ncbi.nlm.nih.gov/pubmed/3300457?dopt=AbstractPlus

148. Myburgh DP, Gordon NF. Comparison of diltiazem and atenolol in young, physically active men with essential hypertension. Am J Cardiol. 1987; 60:1092-5. http://www.ncbi.nlm.nih.gov/pubmed/3314458?dopt=AbstractPlus

149. Szlachcic J, Hirsch AT, Tubau JF et al. Diltiazem versus propranolol in essential hypertension: responses of rest and exercise blood pressure and effects on exercise capacity. Am J Cardiol. 1987; 59:393-9. http://www.ncbi.nlm.nih.gov/pubmed/3812308?dopt=AbstractPlus

150. Weir MR, Josselson J, Giard MJ et al. Sustained-release diltiazem compared with atenolol monotherapy for mild to moderate systemic hypertension. Am J Cardiol. 1987; 60:36-41I. http://www.ncbi.nlm.nih.gov/pubmed/3604943?dopt=AbstractPlus

151. Weiss RJ, Bent B. Diltiazem-induced left ventricular mass regression in hypertensive patients. J Clin Hypertens. 1987; 3:135-43. http://www.ncbi.nlm.nih.gov/pubmed/2956372?dopt=AbstractPlus

152. Schulte KL, Meyer-Sabellek WA, Haertenberger A et al. Antihypertensive and metabolic effects of diltiazem and nifedipine. Hypertension. 1986; 8:859-65. http://www.ncbi.nlm.nih.gov/pubmed/3759224?dopt=AbstractPlus

153. Frishman WH, Zawada ET Jr, Smith LK et al. Comparison of hydrochlorothiazide and sustained-release diltiazem for mild-to-moderate hypertension. Am J Cardiol. 1987; 59:615-23. http://www.ncbi.nlm.nih.gov/pubmed/3548301?dopt=AbstractPlus

154. Leehey DJ, Hartman E. Comparison of diltiazem and hydrochlorothiazide for treatment of patients 60 years of age or older with systemic hypertension. Am J Cardiol. 1988; 62:1218-23. http://www.ncbi.nlm.nih.gov/pubmed/3057851?dopt=AbstractPlus

155. Montamat SC, Abernethy DR. Calcium antagonists in geriatric patients: diltiazem in elderly persons with hypertension. Clin Pharmacol Ther. 1989; 45:682-91. http://www.ncbi.nlm.nih.gov/pubmed/2731407?dopt=AbstractPlus

156. Moser M, Lunn J, Materson BJ. Comparative effects of diltiazem and hydrochlorothiazide in blacks with systemic hypertension. Am J Cardiol. 1985; 56:101-4H.

157. Schulte KL, Meyer-Sabellek W, Rocker L et al. Effects of diltiazem alone and combined with mefruside on cardiovascular response at rest and during exercise, carbohydrate metabolism and serum lipoproteins in patients with systemic hypertension. Am J Cardiol. 1987; 60:826-31. http://www.ncbi.nlm.nih.gov/pubmed/3661396?dopt=AbstractPlus

158. Szlachcic J, Tubau JF, Vollmer C et al. Effect of diltiazem on left ventricular mass and diastolic filling in mild to moderate hypertension. Am J Cardiol. 1989; 63:198-201. http://www.ncbi.nlm.nih.gov/pubmed/2642633?dopt=AbstractPlus

159. Massie BM. Antihypertensive therapy with calcium-channel blockers: comparison with beta blockers. Am J Cardiol. 1985; 56:97-100H.

160. Frishman WH, Charlap S, Goldberger J et al. Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension. Am J Cardiol. 1985; 56:41-6H. http://www.ncbi.nlm.nih.gov/pubmed/4014038?dopt=AbstractPlus

161. Nikkila MT, Inkovaara JA, Heikkinen JT et al. Antihypertensive effect of diltiazem in a slow-release formulation for mild to moderate essential hypertension. Am J Cardiol. 1989; 63:1227-30. http://www.ncbi.nlm.nih.gov/pubmed/2711992?dopt=AbstractPlus

162. Sunderrajan S, Reams G, Bauer JH. Long-term renal effects of diltiazem in essential hypertension. Am Heart J. 1987; 114:383-8. http://www.ncbi.nlm.nih.gov/pubmed/3604896?dopt=AbstractPlus

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164. Tubau JF, Wikman-Coffelt J, Massu BM et al. Diltiazem prevents hypertrophy progression, preserves systolic function, and normalises oxygen utilisation in the spontaneously hypertensive rat. Cardiovasc Res. 1987; 21:606-14. http://www.ncbi.nlm.nih.gov/pubmed/2965615?dopt=AbstractPlus

165. Muller FB, Bolli P, Erne P et al. Use of calcium antagonists as monotherapy in the management of hypertension. Am J Med. 1984; 77(Suppl 2B):11-5. http://www.ncbi.nlm.nih.gov/pubmed/6385691?dopt=AbstractPlus

166. Kiowski W, Bühler FR, Fadayomi MO et al. Age, race, blood pressure and renin: predictors for antihypertensive treatment with calcium antagonists. Am J Cardiol. 1985; 56:81-5H.

167. Frishman WH, Charlap S, Michelson EL. Calcium channel blockers in systemic hypertension. Am J Cardiol. 1986; 58:157-60. http://www.ncbi.nlm.nih.gov/pubmed/3524178?dopt=AbstractPlus

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193. Chellingsworth MC, Kendall MJ, Wright AD et al. The effects of verapamil, diltiazem, nifedipine and propranolol on metabolic control in hypertensives with non-insulin dependent diabetes mellitus. J Hum Hypertens. 1989; 3:35-9.

194. Reams GP, Lau A, Messina C et al. Efficacy, electrocardiographic and renal effects of intravenous diltiazem for essential hypertension. Am J Cardiol. 1987; 60:78-84I.

196. Weber MA, Laragh JH. Hypertension: steps forward and steps backward: the Joint National Committee fifth report. Arch Intern Med. 1993; 153:149-52. http://www.ncbi.nlm.nih.gov/pubmed/8422205?dopt=AbstractPlus

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198. Mantzoros CS, Prabhu AS, Sowers JR. Paralytic ileus as a result of diltiazem treatment. J Int Med. 1994; 235:613-4.

200. Marion Merrell Dow Inc. Cardizem CD (diltiazem HCl) capsules. In: Physicians’ desk reference. 48th ed. Montvale, NJ: Medical Economics Company Inc; 1994(Suppl A):A98.

201. Brodie MJ, Macphee GJA. Carbamazepine neurotoxicity precipitated by diltiazem. BMJ. 1986; 292:1170-1.

202. Eimer M, Carter BL. Elevated serum carbamazepine concentrations following diltiazem initiation. Drug Intell Clin Pharm. 1987; 21:340-2. http://www.ncbi.nlm.nih.gov/pubmed/3569036?dopt=AbstractPlus

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