Diltiazem Hydrochloride

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

Introduction

Calcium-channel blocking agent; nondihydropyridine-derivative.^{271 331}

Uses for Diltiazem Hydrochloride

Angina

Used in the management of Prinzmetal variant angina and chronic stable angina pectoris.^{a 331}

Calcium channel blockers considered the drugs of choice in management of Prinzmetal variant angina.^a

Appears to be as effective as β-adrenergic blocking agents (e.g., propranolol) and/or oral nitrates in the management of chronic stable angina pectoris; however, generally should be used only when the patient cannot tolerate adequate doses of or is refractory to these drugs.^a

Management of unstable angina† in patients who have continuing or ongoing ischemia when therapy with β-blocking agents and nitrates is inadequate, not tolerated, or contraindicated and when severe left ventricular dysfunction, pulmonary edema, or other contraindications are not present.³¹⁵

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).^{138 140 187 188 189 190 195 271 272}

Only extended-release formulations currently are recommended for management of hypertension.²⁷¹

One of several preferred initial therapies for hypertensive patients with a high risk of developing coronary artery disease, including those with diabetes mellitus.³¹⁹

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred for monotherapy by JNC 7.³¹⁹

Supraventricular Tachyarrhythmias

Management of supraventricular tachyarrhythmias, 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 temporary control of rapid ventricular rate in atrial flutter or fibrillation.^{237 238 239 244 245 247 250 252 253 256 257 258 262 270 331}

One of several preferred antiarrhythmic agents for the treatment of stable, narrow-complex supraventricular tachycardias (e.g., paroxysmal supraventricular tachycardia [reentry supraventricular tachycardia], ectopic or multifocal atrial tachycardia†, junctional tachycardia†) if the rhythm is not controlled by vagal maneuvers or adenosine and to control the ventricular response rate in atrial fibrillation or flutter.³³¹

AMI

Calcium-channel blocking agents have not proved beneficial in the early treatment or secondary prevention of AMI† and the possibility that they may be harmful has been raised.^{270 331}

May be used for relief of ongoing ischemia or to control rapid ventricular response with atrial fibrillation after an AMI† when β-adrenergic blocking agents are ineffective or contraindicated, but only in patients in whom there is no evidence of CHF, left-ventricular dysfunction, or AV block and only after weighing carefully the potential benefits versus risks, particularly negative inotropic effects and concerns about short-acting formulations of the drugs.^{270 331}

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

Administration

Administer by direct IV injection, continuous IV infusion, or orally.^{138 187 190 237 270 271 323 331}

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., 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, Dilacor XR, Dilt-XR, Tiazac, Taztia XT, Cartia XT, or Diltia XT may be administered once daily;^{187 190 271 278 324 325 326} 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, Dilacor XR, Diltia XT, and Dilt-XR should be taken on an empty stomach, swallowed whole and not opened, chewed, or crushed.^{190 278 324}

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 Tablet should be swallowed whole and not chewed or crushed.³²³

IV Injection

Monitor ECG and BP continuously during IV administration.²³⁷

Reconstitution

Prepare solutions from the powder for injection (Lyo-Ject) according to the manufacturer's directions.^{237 293}

Dilution

Injection solutions containing 5 mg/mL or powder for injection that has been reconstituted according to manufacturer's directions may be administered by direct IV injection without any further dilution.²³⁷

Rate of Administration

Administer over 2 minutes.²³⁷

IV Infusion

Reconstitution

Prepare solutions from the powder for injection (Lyo-Ject) according to the manufacturer's directions.^{237 293}

Dilution

Dilute 5 mg/mL injection solution or reconstituted powder for injection 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 or Reconstituted Lyo-Ject 5 mg/mL solution.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 (Dilacor XR, Diltia XT, Dilt-XR) or 120–180 mg (Cardizem CD, Cartia XT, Tiazac, Taztia XT) once daily when administered as extended-release capsules.^{187 190 274 278 324 325 326} Individualize dosage based on response; titrate dosage increases over 7–14 days.^{187 190 274 278 324 325 326} Some patients may respond to higher dosages of up to 480 (Cardizem CD, Cartia XT, Dilacor XR, Diltia XT, Dilt-XR) to 540 mg (Tiazac, Taztia XT) once daily.^{187 190 274 278 324 325 326}

Extended-release Tablets

Oral

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

Hypertension

Extended-release Capsules

Oral

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

JNC 7 recommends a usual maximum dosage of 420 mg daily for these preparations.³¹⁹

Recommended Dosages for Management of Hypertension

Preparation	Initial Dosage	Usual Maintenance Dosage
Cardizem LA	180–240 mg once daily323	120–540 mg323
Cardizem CD	180–240 mg once daily187	240–360 mg daily187
Cartia XT	180–240 mg once daily325	240–360 mg daily325
Dilacor XR	180–240 mg once daily190	180–480 mg once daily190
Diltia XT	180–240 mg once daily278	180–480 mg once daily278
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
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 Cardizem CD Extended-release Capsules

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 extended-release tablets at the nearest equivalent daily dosage.^{187 323 325} Subsequent titration of dosage is based on the clinical response of the patient.^{187 323 325}

Conventional Tablets†

Oral

Initially, 30 mg 3 times daily; may be increased to a maximum dosage of 360 mg daily given in 3 or 4 divided doses.^{140 195}

Extended-release Tablets

Oral

Initially, 180–240 mg daily; however, some patients may respond to a lower dosage.³²³ Individualize dosage based on response; maximum hypotensive effect associated with a given dosage level usually is observed within 14 days.³²³ Usual maintenance dosage is 120–540 mg daily;³²³ however, JNC 7 recommends a usual maximum dosage of 420 mg daily.³¹⁹

Supraventricular Tachyarrhythmias

Paroxysmal Supraventricular Tachycardia, Junctional Tachycardia†, Ectopic Tachycardia†, Multifocal Atrial Tachycardia†)

IV

Initially, 15–20 mg (or 0.25 mg/kg) by direct IV injection over 2 minutes.^{237 256 270 331} If response is inadequate (i.e., conversion to normal sinus rhythm does not occur) give a second dose of 20–25 mg (or 0.35 mg/kg) 15 minutes after the initial dose.^{237 257 270 331}

Maintenance infusion: 5–15 mg/hour; titrate dose to heart rate.³³¹

Patients with low body weights should be dosed on a mg/kg basis.²³⁷

Ventricular Rate Control in Atrial Fibrillation and Flutter

IV

Initially, 15–20 mg (or 0.25 mg/kg) by direct IV injection over 2 minutes.^{237 270 331} If response is inadequate, give 20–25 mg (or 0.35 mg/kg) 15 minutes after the initial dose.^{237 246 270 331}

Maintenance infusion: 5–15 mg/hour; titrate dose to heart rate.³³¹

Prescribing Limits

Adults

Angina

Oral

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

Cardizem CD, Dilacor XR, Diltia XT, Dilt-XR, and Cartia XT extended-release capsules: Maximum 480 mg daily.^{187 190 278 324 325}

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

Hypertension

Oral

Cardizem conventional tablets†: Maximum 360 mg daily.^{140 195}

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

Dilt-XR, Dilacor XR, Diltia XT, Taztia XT, and Tiazac extended-release capsules and Cardizem LA extended-release tablets: maximum 540 mg daily.^{190 274 278 323 324 326 a}

However, JNC 7 recommends a usual maximum dosage of 420 mg daily for these preparations.³¹⁹

Supraventricular Tachyarrhythmias

IV

Maintenance infusion: Maximum 15 mg/hour for ≤24 hours.^{237 244 293}

Special Populations

Hepatic Impairment

Supraventricular Tachyarrhythmias

Atrial Fibrillation and Flutter

IV

Maintenance infusion: Dosage requirements may be lower.^{237 245}

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 manufacturers of Dilacor XR, Dilt-XR, and Diltia XT state that patients 60 years of age or older may respond to an initial daily dosage of 120 mg.^{190 278 324}

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 AMI 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

CHF

Risk of CHF, 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}

Injection in single-use (Lyo-Ject) syringes contains benzyl alcohol as a preservative and should not be used in neonates.²³⁷

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
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)	Possible increased mean AUCs and peak plasma concentrations of lovastatin with concomitant use of diltiazem and lovastatin274 301 302 Interaction not observed when diltiazem was used concomitantly with pravastatin274 302	Monitor patients receiving lovastatin concomitantly with diltiazem for evidence of lovastatin toxicity (e.g., rhabdomyolysis, myositis)301 302
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 extended-release tablets	11–18323
Diltiazem hydrochloride extended-release capsules (12 hours)	6–11b

Onset

Following direct IV injection, reductions in heart rate usually occur within 3 minutes^{237 247 252} 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 (Dilacor XR, Diltia XT).^{190 278 294}

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