CONTRAINDICATIONS
Oral
Diltiazem HCl 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.
Injection
Diltiazem HCl Injectable 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 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 (eg,
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 ³0.12 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.
8. In newborns, due to the presence of benzyl alcohol (Diltiazem HCl syringe formulation
only).
WARNINGS
1. Cardiac Conduction: Diltiazem HCl 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 (tablets, six of 1243
patients for 0.48%; SR capsules, 9 of 2111 patients or 0.43%; once-daily capsules, 13 of
3290 patients or 0.40%). 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). Additional Information for Injection: Diltiazem HCl 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 for injectable forms, studies 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 HCl 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. SR and
Once-Daily Capsules: An acute study of oral diltiazem in patients with impaired ventricular
function (ejection fraction 24% ± 6%) showed improvement in indices of ventricular function
without significant decrease in contractile function (dp/dt). Once-Daily Capsules:
Worsening of congestive heart failure has been reported in patients with preexisting
impairment of ventricular function.
3. Hypotension: Decreases in blood pressure associated with diltiazem HCl therapy may
occasionally result in symptomatic hypotension (injection, 3.2%). Injection: 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. These reactions tended to occur early after therapy initiation
(1 to 8 weeks for SR and once-daily capsules) have been reversible upon discontinuation of
drug therapy. The relationship to diltiazem HCl is uncertain in most cases, but probable in
some. (See PRECAUTIONS.) SR and Once-Daily Capsules: Mild elevations of
transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin
have been observed in clinical studies. Such elevations were usually transient and frequently
resolved even with continued diltiazem treatment.
5. Ventricular Premature Beats (VPBs): Injection Only; VPBs may be present on
conversion of PSVT to sinus rhythm with diltiazem HCl injectable. 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 HCl is extensively metabolized by the liver and excreted by the kidneys and in bile. As
with any drug given over prolonged periods, laboratory parameters of renal and hepatic function
should be monitored at regular intervals. 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 subacute and chronic dog and rat studies designed to
produce toxicity, high 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, doses of 20
mg/kg were also associated with hepatic changes; however, these changes were reversible with
continued dosing.
Dermatological events (see ADVERSE REACTIONS) may be transient and may disappear
despite continued use of diltiazem HCl. However, skin eruptions progressing to erythema
multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologic
reaction persist, the drug should be discontinued. Injection: Dermatological 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.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
A 24 month study in rats at oral dosage levels of up to 100 mg/kg/day and a 21-month study in mice
at oral dosage levels of up to 30 mg/kg/day showed no evidence of carcinogenicity. There was also
no mutagenic response in vitro orin vivo in mammalian cell assays or in vitro in bacteria. No
evidence of impaired fertility was observed in a study performed in male and female rats at oral
dosages of up to 100 mg/kg/day.
Pregnancy Category 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 oral
antianginal 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 HCl in pregnant
women only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may
approximate serum levels. If use of diltiazem HCl is deemed essential, an alternative method of
infant feeding should be instituted.
Pediatric Use
Safety and effectiveness in children have not been established.