Diltiazem

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Diltiazem®
Adult Indications and Dosage
Pediatric Indications and Dosage
Contraindications
Warnings
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration and Monitoring
IV Compatibility
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Drug Names
Drug Shortage Status
Price

For patient information regarding Diltiazem, click here.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Sheng Shi, M.D. [2]

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Overview

Diltiazem is a Calcium Channel Blocker that is FDA approved for the prophylaxis of chronic stable angina and angina due to Coronary Artery Spasm (tablet or capsule), hypertension (capsule only), atrial fibrillation or atrial flutter, paroxysmal supraventricular tachycardia (injection only). Common adverse reactions include bradyarrhythmia, peripheral edema, dizziness, headache, cough, fatigue.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Chronic Stable Angina

  • Indication (tablet and capsule)
  • Dosing information (tablet)
  • Dosage must be adjusted to each patient's needs.
  • Initial dosage: 30 mg PO qid, before meals and at bedtime,
  • Dosage should be increased gradually (given in divided doses three or four times daily) at 1- to 2-day intervals until optimum response is obtained.
  • Average optimum dosage range: 180 to 360 mg/day. There are no available data concerning dosage requirements in patients with impaired renal or hepatic function. If the drug must be used in such patients, titration should be carried out with particular caution.
  • Dosing information (capsule)
  • Dosages for the treatment of angina should be adjusted to each patient's needs.
  • Initial dosage: 120 mg to 180 mg PO qd.
  • Individual patients may respond to higher doses of up to 540 mg once daily. When necessary, titration should be carried out over 7 to 14 days.

Hypertension

  • Dosing information (capsule only)
  • Dosage needs to be adjusted by titration to individual patient needs.
  • When used as monotherapy, usual starting doses : 120 to 240 mg PO qd.
  • Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly.
  • Usual dosage range : 120 to 540 mg PO qd. Current clinical experience with ‘’‘540 mg’‘’ dose is limited; however, the dose may be increased to ‘’‘540 mg once daily’‘’.

Atrial Fibrillation or Atrial Flutter

  • Indication (injection only)
  • Temporary control of rapid ventricular rate in atrial fibrillation or atrial flutter. It should not be used in patients with atrial fibrillation or atrial flutter associated with an accessory bypass tract such as in Wolff-Parkinson-White (WPW) syndrome or short PR syndrome.

Concomitant use with Other Cardiovascular Agents.

  • 1.Sublingual Nitroglycerin (NTG). May be taken as required to abort acute anginal attacks during diltiazem hydrochloride therapy.
  • 2. Prophylactic Nitrate Therapy. Diltiazem hydrochloride may be safely co-administered with short- and long-acting nitrates.
  • 3.Beta-blockers (See WARNINGS and PRECAUTIONS.)
  • 4.Antihypertensives. Diltiazem hydrochloride has an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of diltiazem hydrochloride or the concomitant antihypertensives may need to be adjusted when adding one to the other.
  • Hypertensive or anginal patients who are treated with other formulations of diltiazem can safely be switched to diltiazem hydrochloride extended-release capsules at the nearest equivalent total daily dose. Subsequent titration to higher or lower doses may, however, be necessary and should be initiated as clinically indicated.

Paroxysmal Supraventricular Tachycardia

  • Indication (injection only)
  • Rapid conversion of paroxysmal supra ventricular tachycardias (PSVT) to sinus rhythm. This includes AV nodal reentrant tachycardias and reciprocating tachycardias associated with an extranodal accessory pathway such as the WPW syndrome or short PR syndrome. Unless otherwise contraindicated, appropriate vagal maneuvers should be attempted prior to administration of diltiazem hydrochloride injection.
  • The use of diltiazem hydrochloride injection should be undertaken with caution when the patient is compromised hemodynamically or is taking other drugs that decrease any or all of the following: peripheral resistance, myocardial filling, myocardial contractility, or electrical impulse propagation in the myocardium.
  • For either indication and particularly when employing continuous intravenous infusion, the setting should include continuous monitoring of the ECG and frequent measurement of blood pressure. A defibrillator and emergency equipment should be readily available.

In domestic controlled trials in patients with atrial fibrillation or atrial flutter, bolus administration of diltiazem hydrochloride injection was effective in reducing heart rate by at least 20% in 95% of patients. Diltiazem hydrochloride injection rarely converts atrial fibrillation or atrial flutter to normal sinus rhythm. :* :* :* :* :* Following administration of one or two intravenous bolus doses of diltiazem injection, response usually occurs within 3 minutes and maximal heart rate reduction generally occurs in 2 to 7 minutes. Heart rate reduction may last from 1 to 3 hours. If hypotension occurs, it is generally short-lived, but may last from 1 to 3 hours.

  • A 24-hour continuous infusion of diltiazem injection in the treatment of atrial fibrillation or atrial flutter maintained at least a 20% heart rate reduction during the infusion in 83% of patients.
  • Upon discontinuation of infusion, heart rate reduction may last from 0.5 hours to more than 10 hours (median duration 7 hours). Hypotension, if it occurs, may be similarly persistent.
  • In the controlled clinical trials, 3.2% of patients required some form of intervention (typically, use of intravenous fluids or the Trendelenburg position) for blood pressure support following diltiazem hydrochloride injection.
  • In domestic controlled trials, bolus administration of diltiazem hydrochloride injection was effective in converting PSVT to normal sinus rhythm in 88% of patients within 3 minutes of the first or second bolus dose.
  • Symptoms associated with the arrhythmia were improved in conjunction with decreased heart rate or conversion to normal sinus rhythm following administration of diltiazem hydrochloride injection.
  • Dosing information
  • Direct Intravenous Single Injections (Bolus)
  • The initial dose of diltiazem hydrochloride injection should be 0.25 mg/kg actual body weight as a bolus administered over 2 minutes (20 mg is a reasonable dose for the average patient). If response is inadequate, a second dose may be administered after 15 minutes. The second bolus dose of diltiazem hydrochloride injection should be 0.35 mg/kg actual body weight administered over 2 minutes (25 mg is a reasonable dose for the average patient). Subsequent intravenous bolus doses should be individualized for each patient. Patients with low body weights should be dosed on a mg/kg basis. Some patients may respond to an initial dose of 0.15 mg/kg, although duration of action may be shorter. Experience with this dose is limited.
  • Continuous Intravenous Infusion
  • For continued reduction of the heart rate (up to 24 hours) in patients with atrial fibrillation or atrial flutter, an intravenous infusion of diltiazem hydrochloride may be administered. Immediately following bolus administration of 20 mg (0.25 mg/kg) or 25 mg (0.35 mg/kg) diltiazem hydrochloride injection and reduction of heart rate, begin an intravenous infusion of diltiazem hydrochloride. The recommended initial infusion rate of diltiazem hydrochloride is 10 mg/h. Some patients may maintain response to an initial rate of 5 mg/h. The infusion rate may be increased in 5 mg/h increments up to 15 mg/h as needed, if further reduction in heart rate is required. The infusion may be maintained for up to 24 hours.
  • Diltiazem shows dose-dependent, non-linear pharmacokinetics. Duration of infusion longer than 24 hours and infusion rates greater than 15 mg/h have not been studied. Therefore, infusion duration exceeding 24 hours and infusion rates exceeding 15 mg/h are not recommended.
  • Dilution: To prepare diltiazem hydrochloride injection for continuous intravenous infusion, aseptically transfer the appropriate quantity (see chart) of diltiazem hydrochloride injection to the desired volume of either Normal Saline, D5W, or D5W/0.45% NaCl. Mix thoroughly. Use within 24 hours. Keep refrigerated until use.
This image is provided by the National Library of Medicine.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Unstable Angina

  • Level of Evidence: Not applicable
  • Dosing Information
  • 20 mg IV

Non–Guideline-Supported Use

Anal fissure

  • Dosing information

Coronary artery bypass graft

  • Dosing information

Diabetic nephropathy

  • Dosing information
  • Not applicable

Nephrotoxicity - Post-Transplantation

  • Dosing information
  • 1 mg/kg/min IV [5]
  • 60 mg TID [6]

Hyperthyroidism

  • Dosing information
  • 120 mg q8h [7]
  • 60 mg TID [8]

Prophylaxis of Migraine

  • Dosing information
  • 60 -90 mg PO qid [9]

Myocardial infarction

  • Dosing information

Painful spasm of anus

Pulmonary hypertension

  • Dosing information

Ventricular arrhythmia

  • Dosing information
  • 120- 240 mg/day[15]

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Diltiazem in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Diltiazem in pediatric patients.

Contraindications

Diltiazem in all forms is contraindicated in (1) patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker, (2) patients with second-or third-degree AV block except in the presence of a functioning ventricular pacemaker, (3) patients with hypotension (less than 90 mm Hg systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5) patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.

Diltiazem in injection is contraindicated in

(6) Patients with atrial fibrillation or atrial flutter associated with an accessory bypass tract such as in WPW syndrome or short PR syndrome. As with other agents which slow AV nodal conduction and do not prolong the refractoriness of the accessory pathway (e.g., verapamil, digoxin), in rare instances patients in atrial fibrillation or atrial flutter associated with an accessory bypass tract may experience a potentially life-threatening increase in heart rate accompanied by hypotension when treated with diltiazem hydrochloride injection. As such, the initial use of diltiazem hydrochloride injection should be, if possible, in a setting where monitoring and resuscitation capabilities, including DC cardioversion/defibrillation, are present (see OVERDOSAGE). Once familiarity of the patient’s response is established, use in an office setting may be acceptable. (7) Patients with ventricular tachycardia. Administration of other calcium channel blockers to patients with wide complex tachycardia (QRS≥0.12 seconds) has resulted in hemodynamic deterioration and ventricular fibrillation. It is important that an accurate pretreatment diagnosis distinguish wide complex QRS tachycardia of supraventricular origin from that of ventricular origin prior to administration of diltiazem hydrochloride injection.

Warnings

Diltiazem in all forms:

1. Cardiac Conduction. Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second-or third-degree AV block (six of 1243 patients for 0.48%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem (see ADVERSE REACTIONS).

2. Congestive Heart Failure. Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). Experience with the use of Diltiazem alone or in combination with beta-blockers in patients with impaired ventricular function is very limited. Caution should be exercised when using the drug in such patients.

3. Hypotension. Decreases in blood pressure associated with Diltiazem therapy may occasionally result in symptomatic hypotension.

4. Acute Hepatic Injury. In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions have been reversible upon discontinuation of drug therapy. The relationship to Diltiazem is uncertain in most cases, but probable in some (see PRECAUTIONS).

Diltiazem injection:

5. Ventricular Premature Beats (VPBs). VPBs may be present on conversion of PSVT to sinus rhythm with diltiazem hydrochloride injection. These VPBs are transient, are typically considered to be benign, and appear to have no clinical significance. Similar ventricular complexes have been noted during cardioversion, other pharmacologic therapy, and during spontaneous conversion of PSVT to sinus rhythm.

Adverse Reactions

Clinical Trials Experience

Serious adverse reactions have been rare in studies carried out to date, but it should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities usually have been excluded.

In domestic placebo-controlled angina trials, the incidence of adverse reactions reported during Diltiazem therapy was not greater than that reported during placebo therapy.

The following represent occurrences observed in clinical studies of angina patients. In many cases, the relationship to Diltiazem has not been established. The most common occurrences from these studies, as well their frequency of presentation, are edema (2.4%), headache (2.1%), nausea (1.9%), dizziness (1.5%), rash (1.3%), and asthenia (1.2%). In addition, the following events were reported infrequently (less than 1 %):

Cardiovascular: Angina, arrhythmia, AV block ( first-degree), AV block (second- or third-degree – see WARNINGS, Cardiac Conduction), bradycardia, bundle branch block, congestive heart failure, ECG abnormality, flushing, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.

Nervous System: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tremor.

Gastrointestinal: Anorexia, constipation, diarrhea, dysgeusia, dyspepsia, mild elevations of alkaline phosphatase, SGOT, SGPT, and LDH (see WARNINGS, Acute Hepatic Injury), thirst, vomiting, weight increase.

Dermatological: Petechiae, photosensitivity, pruritus, urticaria.

Other: Amblyopia, CPK elevation, dry mouth, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties, tinnitus.

Postmarketing Experience

The following postmarketing events have been reported infrequently in patients receiving Diltiazem: acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema (including facial or periorbital edema), asystole, erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), purpura, retinopathy, myopathy, and thrombocytopenia. There have been observed cases of a generalized rash, some characterized as leukocytoclastic vasculitis. In addition, events such as myocardial infarction have been observed, which are not readily distinguishable from the natural history of the disease in these patients. A definitive cause and effect relationship between these events and Diltiazem therapy cannot yet be established. Exfoliative dermatitis (proven by rechallenge) has also been reported.


Drug Interactions

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving Diltiazem concomitantly with any agents known to affect cardiac contractility and/or conduction (see WARNINGS). Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with Diltiazem (see WARNINGS). As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem is both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are specific substrates, inhibitors, or inducers of this enzyme system may have a significant impact on the efficacy and side effect profile of diltiazem. Patients taking other drugs that are substrates of CYP450 3A4, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping concomitantly administered diltiazem in order to maintain optimum therapeutic blood levels.

Anesthetics.

The depression of cardiac contractility, conductivity, and automaticity, as well as the vascular dilation associated with anesthetics, may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.

Benzodiazepines.

Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3- to 4-fold and the Cmax by 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam also increased (1.5- to 2.5-fold) during coadministration with diltiazem. These pharmacokinetic effects seen during diltiazem coadministration can result in increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam.

Beta-blockers.

Controlled and uncontrolled domestic studies suggest that concomitant use of Diltiazem and beta-blockers is usually well tolerated. Available data are not sufficient, however, to predict the effects of concomitant treatment, particularly in patients with left ventricular dysfunction or cardiac conduction abnormalities.

Administration of Diltiazem (diltiazem hydrochloride) concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects, and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its binding sites by diltiazem. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (see WARNINGS).

Buspirone.

In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and Cmax 4.1-fold compared to placebo. The T1/2 and Tmax of buspirone were not significantly affected by diltiazem. Enhanced effects and increased toxicity of buspirone may be possible during concomitant administration with diltiazem. Subsequent dose adjustments may be necessary during coadministration, and should be based on clinical assessment.

Carbamazepine.

Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40% to 72% increase) resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.

Cimetidine.

A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1-week course of cimetidine at 1200 mg per day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, the enzyme system responsible for the first-pass metabolism of diltiazem. Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. An adjustment in the diltiazem dose may be warranted.

Clonidine.

Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with diltiazem. Monitor heart rate in patients receiving concomitant diltiazem and clonidine.

Cyclosporine.

A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine trough dose ranging from 15% to 48% was necessary to maintain concentrations similar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted, or discontinued. The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.

Digitalis.

Administration of Diltiazem with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Since there have been conflicting results regarding the effect of digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing Diltiazem therapy to avoid possible over- or under-digitalization (see WARNINGS).

Quinidine.

Diltiazem significantly increases the AUC (0→∞) of quinidine by 51%, T1/2 by 36%, and decreases its CLoral by 33%. Monitoring for quinidine adverse effects may be warranted and the dose adjusted accordingly.

Rifampin.

Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels. Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered.

Statins.

Diltiazem is an inhibitor of CYP3A4 and has been shown to increase significantly the AUC of some statins. The risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4 may be increased with concomitant use of diltiazem. When possible, use a non-CYP3A4-metabolized statin together with diltiazem; otherwise, dose adjustments for both diltiazem and the statin should be considered along with close monitoring for signs and symptoms of any statin related adverse events.

In a healthy volunteer cross-over study (N=10), co-administration of a single 20 mg dose of simvastatin at the end of a 14 day regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of diltiazem showed a greater fold increase in simvastatin exposure. Computer-based simulations showed that at a daily dose of 480 mg of diltiazem, an 8- to 9-fold mean increase in simvastatin AUC can be expected. If co-administration of simvastatin with diltiazem is required, limit the daily doses of simvastatin to 10 mg and diltiazem to 240 mg.

In a ten-subject randomized, open label, 4-way cross-over study, co-administration of diltiazem (120 mg BID diltiazem SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3- to 4-fold increase in mean lovastatin AUC and Cmax versus lovastatin alone. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and Cmax during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C

Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from five to ten times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studies, there was some reduction in early individual pup weights and survival rates. There was an increased incidence of stillbirths at doses of 20 times the human dose or greater.

There are no well-controlled studies in pregnant women; therefore, use Diltiazem in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Category (AUS):

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Diltiazem in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Diltiazem during labor and delivery.

Nursing Mothers

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of Diltiazem is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatic Use

Clinical studies of diltiazem did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Gender

There is no FDA guidance on the use of Diltiazem with respect to specific gender populations.

Race

There is no FDA guidance on the use of Diltiazem with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Diltiazem in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Diltiazem in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Diltiazem in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Diltiazem in patients who are immunocompromised.


Administration and Monitoring

Administration

Oral, intravenous

Monitoring

FDA Package Insert for Diltiazem contains no information regarding drug monitoring.

IV Compatibility

Compatibility: Diltiazem hydrochloride injection was tested for compatibility with three commonly used intravenous fluids at a maximal concentration of 1 mg diltiazem hydrochloride per milliliter. Diltiazem hydrochloride injection was found to be physically compatible and chemically stable in the following parenteral solutions for at least 24 hours when stored in glass or polyvinylchloride (PVC) bags at controlled room temperature 15° to 30°C (59° to 86°F) or under refrigeration 2° to 8°C (36° to 46°F).

  • dextrose (5%) injection
  • sodium chloride (0.9%) injection
  • dextrose (5%) and sodium chloride (0.45%) injection

Physical Incompatibilities: Because of potential physical incompatibilities, it is recommended that diltiazem hydrochloride not be mixed with any other drugs in the same container. If possible, it is recommended that diltiazem hydrochloride not be co-infused in the same intravenous line. Physical incompatibilities (precipitate formation or cloudiness) were observed when diltiazem hydrochloride injection was infused in the same intravenous line with the following drugs: acetazolamide, acyclovir, aminophylline, ampicillin, ampicillin sodium/sulbactam sodium, cefamandole, cefoperazone, diazepam, furosemide, hydrocortisone sodium succinate, insulin (regular: 100 units/mL), methylprednisolone sodium succinate, mezlocillin, nafcillin, phenytoin, rifampin, and sodium bicarbonate. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Overdosage

The oral LD50s in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50s in these species were 60 and 38 mg/kg, respectively. The oral LD50 in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg.

The toxic dose in man is not known. Due to extensive metabolism, blood levels after a standard dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases.

There have been reports of diltiazem overdose in amounts ranging from <1 g to 18 g. Of cases with known outcome, most patients recovered and in cases with a fatal outcome, the majority involved multiple drug ingestion.

Events observed following diltiazem overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine, as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure, and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium.

The effectiveness of intravenous calcium administration to reverse the pharmacological effects of diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium channel blockers associated with hypotension and bradycardia that was initially refractory to atropine became more responsive to atropine after the patients received intravenous calcium. In some cases intravenous calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes and repeated every 10 to 20 minutes as necessary. Calcium gluconate has also been administered as a continuous infusion at a rate of 2 g per hour for 10 hours. Infusions of calcium for 24 hours or more may be required. Patients should be monitored for signs of hypercalcemia.

In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination following overdose. Based on the known pharmacological effects of diltiazem and/or reported clinical experiences, the following measures may be considered:

Bradycardia: Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.

High-Degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.

Cardiac Failure: Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.

Hypotension: Vasopressors (e.g., dopamine or norepinephrine).

Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.

Pharmacology

Diltiazem structure.png
Diltiazem ball-and-stick.png
Diltiazem
Systematic (IUPAC) name
cis-(+)-[2-(2-dimethylaminoethyl)-5-(4-methoxyphenyl)
-3-oxo-6-thia-2-azabicyclo[5.4.0]undeca-7,9,
11-trien-4-yl]ethanoate
Identifiers
CAS number 42399-41-7
ATC code C08DB01
PubChem 39186
DrugBank DB00343
Chemical data
Formula C22H26N2O4S 
Mol. mass 414.519 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 40%
Metabolism Hepatic
Half life 3–4.5 hours
Excretion Renal
Biliary
Lactic (in lactating females)
Therapeutic considerations
Pregnancy cat.

C: (USA)

Legal status
Routes Oral

Mechanism of Action

Diltiazem inhibits the influx of calcium (Ca2+) ions during membrane depolarization of cardiac and vascular smooth muscle. The therapeutic benefits of diltiazem in supraventricular tachycardias are related to its ability to slow AV nodal conduction time and prolong AV nodal refractoriness. Diltiazem exhibits frequency (use) dependent effects on AV nodal conduction such that it may selectively reduce the heart rate during tachycardias involving the AV node with little or no effect on normal AV nodal conduction at normal heart rates. Diltiazem slows the ventricular rate in patients with a rapid ventricular response during atrial fibrillation or atrial flutter. Diltiazem converts Paroxysmal Supraventricular Tachycardia (PSVT) to normal sinus rhythm by interrupting the reentry circuit in AV nodal reentrant tachycardias and reciprocating tachycardias, e.g., Wolff-Parkinson-White syndrome (WPW). Diltiazem prolongs the sinus cycle length. It has no effect on the sinus node recovery time or on the sinoatrial conduction time in patients without SA nodal dysfunction. Diltiazem has no significant electrophysiologic effect on tissues in the heart that are fast sodium channel dependent, e.g., His-Purkinje tissue, atrial and ventricular muscle, and extranodal accessory pathways. Like other calcium channel antagonists, because of its effect on vascular smooth muscle, diltiazem decreases total peripheral resistance resulting in a decrease in both systolic and diastolic blood pressure.

Structure

Diltiazem® (diltiazem hydrochloride) is a calcium ion cellular influx inhibitor (slow channel blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride,(+)-cis-. The chemical structure is:

This image is provided by the National Library of Medicine.

Pharmacodynamics

Like other calcium antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.

In man, diltiazem prevents spontaneous and ergonovine-provoked Coronary Artery Spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure, and in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given workload. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end-diastolic pressure have not been affected. There are as yet few data on the interaction of diltiazem and beta-blockers. Resting heart rate is usually unchanged or slightly reduced by diltiazem.

Intravenous diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods approximately 20%. In a study involving single oral doses of 300 mg of Diltiazem in six normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first-degree AV block. Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

Chronic oral administration of Diltiazem in doses of up to 240 mg/day has resulted in small increases in PR interval but has not usually produced abnormal prolongation.

Pharmacokinetics

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous dosing) of about 40%. Diltiazem undergoes extensive metabolism in which 2% to 4% of the unchanged drug appears in the urine. In vitro binding studies show Diltiazem is 70% to 80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown Diltiazem binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0 to 4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of 10% to 20% of the parent drug and is 25% to 50% as potent as a coronary vasodilator as diltiazem. Minimum therapeutic plasma levels of Diltiazem appear to be in the range of 50 to 200 ng/mL. There is a departure from linearity when dose strengths are increased. A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in AUC (area-under-the-plasma concentration vs time curve) in the hepatically impaired patients. A single study in nine patients with severely impaired renal functions showed no difference in the pharmacokinetic profile of diltiazem as compared to patients with normal renal function.

Diltiazem Tablets. Diltiazem is absorbed from the tablet formulation to about 98% of a reference solution. Single oral doses of 30 to 120 mg of Diltiazem tablets result in detectable plasma levels within 30 to 60 minutes and peak plasma levels 2 to 4 hours after drug administration. As the dose of Diltiazem tablets is increased from a daily dose of 120 mg (30 mg qid) to 240 mg (60 mg qid) daily, there is an increase in area-under-the-curve of 2.3 times. When the dose is increased from 240 mg to 360 mg, daily, there is an increase in area-under-the-curve of 1.8 times.

Nonclinical Toxicology

A 24-month study in rats and a 21-month study in mice showed no evidence of carcinogenicity. There was also no mutagenic response in in vitro bacterial tests. No intrinsic effect on fertility was observed in rats

Clinical Studies

FDA Package Insert for Diltiazem contains no information regarding clinical studies.

How Supplied

Tablet

Diltiazem 30-mg tablets are supplied in bottles of 100 (NDC 0187-0771-47) and 500 (NDC 0187-0771-55). Each light green, round tablet is engraved with MARION on one side and 1771 on the other. Diltiazem 60-mg scored tablets are supplied in bottles of 100 (NDC 0187-0772-47). Each light yellow, round tablet is engraved with MARION on one side and 1772 on the other. Diltiazem 90-mg scored tablets are supplied in bottles of 100 (NDC 0187-0791-47). Each green, oblong tablet is engraved with Diltiazem on one side and 90 mg on the other. Diltiazem 120-mg scored tablets are supplied in bottles of 100 (NDC 0187-0792-47). Each light yellow, capsule-shaped tablet is engraved with Diltiazem on one side and 120 mg on the other.

Capsule

This image is provided by the National Library of Medicine.

Injection

Diltiazem Hydrochloride Injection is supplied as follows: NDC 55390-565-05 - 5 mL vials with each vial containing 25 mg (5 mg/mL) of diltiazem hydrochloride; box of 10. NDC 55390-565-10 - 10 mL vials with each vial containing 50 mg (5 mg/mL) of diltiazem hydrochloride; box of 10. NDC 55390-565-30 - 25 mL vials with each vial containing 125 mg (5 mg/mL) of diltiazem hydrochloride; box of 10.

Storage

Tablet

Store at 25°C (77°); excursions permitted to 15-30°C (59-86°) [see USP Controlled Room Temperature].

Capsule

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Avoid excessive humidity.

Injection

STORE PRODUCT UNDER REFRIGERATION 2° TO 8°C (36° TO 46°F). DO NOT FREEZE. MAY BE STORED AT ROOM TEMPERATURE FOR UP TO 1 MONTH. DESTROY AFTER 1 MONTH AT ROOM TEMPERATURE. SINGLE USE VIALS. DISCARD UNUSED PORTION.

Images

Drug Images

Diltiazem 120 mg NDC 0258-3687.jpg

Drug Name: Diltiazem
Ingredient(s): cellulose, microcrystalline, sucrose, povidone, talc, magnesium stearate, hypromellose, titanium dioxide, gelatin, fd&c blue no. 1, fd&c red no. 40, d&c red no. 28, fd&c green no. 3, ferrosoferric oxide
Imprint: 420
Dosage: 120 mg
Color(s): Purple
Shape: Capsule
Size (mm): 16
Score: 1
NDC:0258-3687

Drug Label Author: Forest Laboratories, Inc.

This pill image is provided by the National Library of Medicine's PillBox.
Diltiazem 180 mg NDC 0258-3688.jpg

Drug Name: Diltiazem
Ingredient(s): cellulose, microcrystalline, sucrose, povidone, talc, magnesium stearate, hypromellose, titanium dioxide, gelatin, fd&c blue no. 1, fd&c red no. 40, d&c red no. 28, fd&c green no. 3, ferrosoferric oxide
Imprint: 180
Dosage: 180 mg
Color(s): Blue
Shape: Capsule
Size (mm): 18
Score: 1
NDC:0258-3688

Drug Label Author: Forest Laboratories, Inc.

This pill image is provided by the National Library of Medicine's PillBox.
Diltiazem 240 mg NDC 0258-3689.jpg

Drug Name: Diltiazem
Ingredient(s): cellulose, microcrystalline, sucrose, povidone, talc, magnesium stearate, hypromellose, titanium dioxide, gelatin, fd&c blue no. 1, fd&c red no. 40, d&c red no. 28, fd&c green no. 3, ferrosoferric oxide
Imprint: 240
Dosage: 240 mg
Color(s): Purple
Shape: Capsule
Size (mm): 19
Score: 1
NDC:0258-3689

Drug Label Author:

This pill image is provided by the National Library of Medicine's PillBox.
Diltiazem 300 mg NDC 0258-3690.jpg

Drug Name: Diltiazem
Ingredient(s): cellulose, microcrystalline, sucrose, povidone, talc, magnesium stearate, hypromellose, titanium dioxide, gelatin, fd&c blue no. 1, fd&c red no. 40, d&c red no. 28, fd&c green no. 3, ferrosoferric oxide
Imprint: 300
Dosage: 300 mg
Color(s): Purple
Shape: Capsule
Size (mm): 22
Score: 1
NDC:0258-3690

Drug Label Author: Forest Laboratories, Inc.

This pill image is provided by the National Library of Medicine's PillBox.
Diltiazem 360 mg NDC 0258-3691.jpg

Drug Name: Diltiazem
Ingredient(s): cellulose, microcrystalline, sucrose, povidone, talc, magnesium stearate, hypromellose, titanium dioxide, gelatin, fd&c blue no. 1, fd&c red no. 40, d&c red no. 28, fd&c green no. 3, ferrosoferric oxide
Imprint: 360
Dosage: 360 mg
Color(s): Green
Shape: Capsule
Size (mm): 22
Score: 1
NDC:0258-3691

Drug Label Author: Forest Laboratories, Inc.

This pill image is provided by the National Library of Medicine's PillBox.

Package and Label Display Panel

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Patient Counseling Information

Precautions with Alcohol

Alcohol-Diltiazem interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

  • Cardizem
  • Cardizem CD
  • Cartia XT
  • Dilacor XR
  • Tiazac
  • Dilt-CD
  • Dilt-XR
  • Diltia XT

Look-Alike Drug Names

Dilacor XR - Pilocar Tiazac - Ziac[16]

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. Carapeti EA, Kamm MA, Phillips RK (2000). "Topical diltiazem and bethanechol decrease anal sphincter pressure and heal anal fissures without side effects.". Dis Colon Rectum 43 (10): 1359-62. PMID 11052511.
  2. Jonas M, Neal KR, Abercrombie JF, Scholefield JH (2001). "A randomized trial of oral vs. topical diltiazem for chronic anal fissures.". Dis Colon Rectum 44 (8): 1074-8. PMID 11535842.
  3. Christakis GT, Fremes SE, Weisel RD, Tittley JG, Mickle DA, Ivanov J et al. (1986). "Diltiazem cardioplegia. A balance of risk and benefit.". J Thorac Cardiovasc Surg 91 (5): 647-61. PMID 3517506.
  4. Costa P, Donegani E, DePaulis R, Ottino GM, Villani M, Matani A et al. (1986). "Diltiazem cold cardioplegia in coronary artery surgery: effects on myocardial function and ischemia.". Tex Heart Inst J 13 (1): 53-60. PMID 15226832.
  5. Dönmez A, Karaaslan D, Sekerci S, Akpek E, Karakayali H, Arslan G (1999). "The effects of diltiazem and dopamine on early graft function in renal transplant recipients.". Transplant Proc 31 (8): 3305-6. PMID 10616487.
  6. Choy BY, Walker RG, Becker GJ (1994). "Vasculopathy in cyclosporine-treated renal allografts: possible protection by diltiazem.". Clin Transplant 8 (3 Pt 1): 271-3. PMID 8061366.
  7. Roti E, Montermini M, Roti S, Gardini E, Robuschi G, Minelli R et al. (1988). "The effect of diltiazem, a calcium channel-blocking drug, on cardiac rate and rhythm in hyperthyroid patients.". Arch Intern Med 148 (9): 1919-21. PMID 2458079.
  8. Milner MR, Gelman KM, Phillips RA, Fuster V, Davies TF, Goldman ME (1990). "Double-blind crossover trial of diltiazem versus propranolol in the management of thyrotoxic symptoms.". Pharmacotherapy 10 (2): 100-6. PMID 2349134.
  9. Smith R, Schwartz A (1984). "Diltiazem prophylaxis in refractory migraine.". N Engl J Med 310 (20): 1327-8. doi:10.1056/NEJM198405173102015. PMID 6144044.
  10. (1998) "Correction: Outcomes in Patients with Acute Non-Q-Wave Myocardial Infarction Randomly Assigned to an Invasive as Compared with a Conservative Management Strategy.". N Engl J Med 339 (15): 1091. doi:10.1056/NEJM199810083391520. PMID 9761812.
  11. Ogawa H, Yasue H, Nakamura N, Obata K, Sonoda R (1987). "Hemodynamic effects of intravenous diltiazem in patients with acute myocardial infarction.". Clin Cardiol 10 (6): 323-8. PMID 3594955.
  12. Boquet J, Moore N, Lhuintre JP, Boismare F (1986). "Diltiazem for proctalgia fugax.". Lancet 1 (8496): 1493. PMID 2873295.
  13. Kambara H, Fujimoto K, Wakabayashi A, Kawai C (1981). "Primary pulmonary hypertension: beneficial therapy with diltiazem.". Am Heart J 101 (2): 230-1. PMID 7468425.
  14. Shinohara S, Murata I, Yamada H, Sato T, Kikutani T, Inoue T et al. (1994). "Combined effects of diltiazem and oxygen in pulmonary hypertension of mixed connective tissue disease.". J Rheumatol 21 (9): 1763-5. PMID 7799364.
  15. Papademetriou V, Narayan P, Kokkinos P (1994). "Effects of diltiazem, metoprolol, enalapril and hydrochlorothiazide on frequency of ventricular premature complexes.". Am J Cardiol 73 (4): 242-6. PMID 7507638.
  16. https://www.ismp.org.

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