Diltiazem Hydrochloride (Page 2 of 6)

INDICATIONS AND USAGE

Diltiazem Hydrochloride Injection or Diltiazem Hydrochloride for Injection are indicated for the following:

Atrial Fibrillation or Atrial Flutter

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.

In addition, Diltiazem Hydrochloride Injection is indicated for:

Paroxysmal Supraventricular Tachycardia

Rapid conversion of paroxysmal supraventricular 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 or diltiazem hydrochloride for 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 hydrochloride 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 hydrochloride 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.

CONTRAINDICATIONS

Injectable forms of diltiazem are 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 severe hypotension or cardiogenic shock.
  4. Patients who have demonstrated hypersensitivity to the drug.
  5. Intravenous diltiazem and intravenous beta-blockers should not be administered together or in close proximity (within a few hours).
  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 injectable forms of diltiazem. As such, the initial use of injectable forms of diltiazem 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 injectable forms of diltiazem.

WARNINGS

  1. Cardiac Conduction. Diltiazem prolongs AV nodal conduction and refractoriness that may rarely result in second- or third-degree AV block in sinus rhythm. Concomitant use of diltiazem with agents known to affect cardiac conduction may result in additive effects (see Drug Interactions). If high-degree AV block occurs in sinus rhythm, intravenous diltiazem should be discontinued and appropriate supportive measures instituted (see OVERDOSAGE).
  2. Congestive Heart Failure. Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function and in patients with a compromised myocardium, such as severe CHF, acute MI, and hypertrophic cardiomyopathy, have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). Administration of oral diltiazem in patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission is contraindicated. Experience with the use of diltiazem hydrochloride injection in patients with impaired ventricular function is limited. Caution should be exercised when using the drug in such patients.
  3. Hypotension. Decreases in blood pressure associated with diltiazem hydrochloride injection therapy may occasionally result in symptomatic hypotension (3.2%). The use of intravenous diltiazem for control of ventricular response in patients with supraventricular arrhythmias should be undertaken with caution when the patient is compromised hemodynamically. In addition, caution should be used in patients taking other drugs that decrease peripheral resistance, intravascular volume, myocardial contractility or conduction.
  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 following oral diltiazem. Therefore, the potential for acute hepatic injury exists following administration of intravenous diltiazem.
  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.

PRECAUTIONS

General

Diltiazem hydrochloride is extensively metabolized by the liver and excreted by the kidneys and in bile. The drug should be used with caution in patients with impaired renal or hepatic function (see WARNINGS). High intravenous dosages (4.5 mg/kg tid) administered to dogs resulted in significant bradycardia and alterations in AV conduction. In subacute and chronic dog and rat studies designed to produce toxicity, high oral doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver, which were reversible when the drug was discontinued. In dogs, oral doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.

Dermatologic events progressing to erythema multiforme and/or exfoliative dermatitis have been infrequently reported following oral diltiazem. Therefore, the potential for these dermatologic reactions exists following exposure to intravenous diltiazem. Should a dermatologic reaction persist, the drug should be discontinued.

Drug Interactions

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.

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