Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2072
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Diltiazem Hydrochloride (Powder, For Solution)
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NOTE: This drug product
is not for direct bolus injection. Text referring to direct bolus injection
is provided for information purposes only. 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 injection.
The recommended initial infusion rate of diltiazem hydrochloride injection
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 for
Injection for continuous intravenous infusion, assemble the ADD-Vantage vial
as directed for use with either 0.9% Sodium Chloride or Dextrose (5%) injection.
Mix thoroughly. Keep diluted Diltiazem Hydrochloride for Injection at controlled
room temperature (15��to 30��C) (59��to 86��F) [See USP.]
or refrigerated (2��to 8��C) (36��to 46��F) until use. Use
within 24 hours. *5 mg/h may be appropriate for some patients. INSTRUCTIONS FOR USE To Use Vial in ADD-VantageFlexible Diluent Container To Open: Peel overwrap at
corner and remove solution container. Some opacity of the plastic due to moisture
absorption during the sterilization process may be observed. This is normal
and does not affect the solution quality or safety. The opacity will diminish
gradually. To Assemble Vial
and Flexible Diluent Container: (Use
Aseptic Technique) To Reconstitute the Drug: Preparation for Administration: (Use Aseptic Technique) WARNING: Do not use flexible containers
in series connections. 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 polyvinylchloride
(PVC) bags at controlled room temperature 20 to 25��C (68 to 77��F)
[see USP] or under refrigeration 2 to 8��C (36 to 46��F). *
dextrose (5%) injection, USP * sodium chloride (0.9%)
injection, USP * dextrose (5%) and sodium chloride (0.45%)
injection, USP 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 coinfused in the same intravenous line. Parenteral drug
products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit. Diltiazem hydrochloride. Physical incompatibilities
(precipitate formation or cloudiness) were observed when diltiazem hydrochloride
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. NOTE: Diltiazem Hydrochloride for Injection at
a concentration of 1 mg/mL diluted in normal saline was infused in the same
intravenous line and was found to be compatible with the following drugs:
aminophylline, ampicillin sodium, ampicillin sodium/sulbactam sodium, cefamandole,
hydrocortisone sodium succinate, regular insulin (100 units/mL), methylprednisolone
sodium succinate, mezlocillin sodium, nafcillin sodium and sodium bicarbonate. Transition to Further Antiarrhythmic Therapy: Transition
to other antiarrhythmic agents following administration of diltiazem hydrochloride
injection is generally safe. However, reference should be made to the respective
agent manufacturer's package insert for information relative to dosage
and administration. In controlled clinical trials, therapy
with antiarrhythmic agents to maintain reduced heart rate in atrial fibrillation
or atrial flutter or for prophylaxis of PSVT was generally started within
3 hours after bolus administration of diltiazem. These antiarrhythmic agents
were intravenous or oral digoxin, Class 1 antiarrhythmics (e.g., quinidine,
procainamide), calcium channel blockers, and oral beta-blockers. Experience
in the use of antiarrhythmic agents following maintenance infusion of diltiazem
hydrochloride injection is limited. Patients should be dosed on an individual
basis and reference should be made to the respective manufacturer's
package insert for information relative to dosage and administration.
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Diltiazem Hydrochloride for Injection is a calcium ion influx
inhibitor (slow channel blocker or calcium channel 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: Diltiazem hydrochloride is a white to off-white crystalline
powder with a bitter taste. It is soluble in water, methanol, and chloroform.
It has a molecular weight of 450.98. Diltiazem Hydrochloride
for Injection, after reconstitution in an infusion bag, produces a clear,
colorless, sterile, nonpyrogenic solution. The vials
contain sterile diltiazem hydrochloride, USP, 100 mg and mannitol, USP, 75
mg base for reconstitution in the ADD-Vantage Flexible Diluent Container containing 5% dextrose injection or
0.9% sodium chloride injection. Diltiazem hydrochloride is an off-white lyophilized
powder. When reconstituted in an infusion bag, it produces a clear, colorless,
sterile, nonpyrogenic solution. Diltiazem hydrochloride is intended to be
used as continuous intravenous infusion with the ADD-Vantage Flexible Diluent Container.
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Mechanisms of Action Diltiazem
inhibits the influx of calcium (Ca) 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 effects 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. Hemodynamics In patients with cardiovascular disease,
diltiazem hydrochloride injection administered intravenously in single bolus
doses, followed in some cases by a continuous infusion, reduced blood pressure,
systemic vascular resistance, the rate-pressure product, and coronary vascular
resistance and increased coronary blood flow. In a limited number of studies
of patients with compromised myocardium (severe congestive heart failure,
acute myocardial infarction, hypertrophic cardiomyopathy), administration
of intravenous diltiazem produced no significant effect on contractility,
left ventricular end diastolic pressure, or pulmonary capillary wedge pressure.
The mean ejection fraction and cardiac output/index remained unchanged or
increased. Maximal hemodynamic effects usually occurred within 2 to 5 minutes
of an injection. However, in rare instances, worsening of congestive heart
failure has been reported in patients with preexisting impaired ventricular
function. Pharmacodynamics The prolongation of PR interval correlated
significantly with plasma diltiazem concentration in normal volunteers using
the Sigmoidal Emodel. Changes in heart rate, systolic blood
pressure, and diastolic blood pressure did not correlate with diltiazem plasma
concentrations in normal volunteers. Reduction in mean arterial pressure correlated
linearly with diltiazem plasma concentration in a group of hypertensive patients. In
patients with atrial fibrillation and atrial flutter, a significant correlation
was observed between the percent reduction in HR and plasma diltiazem concentration
using the Sigmoidal Emodel. Based on this relationship, the
mean plasma diltiazem concentration required to produce a 20% decrease in
heart rate was determined to be 80 ng/mL. Mean plasma diltiazem concentrations
of 130 ng/mL and 300 ng/mL were determined to produce reductions in heart
rate of 30% and 40%. Pharmacokinetics
and Metabolism Following a single intravenous
injection in healthy male volunteers, diltiazem hydrochloride appears to obey
linear pharmacokinetics over a dose range of 10.5 to 21 mg. The plasma elimination
half-life is approximately 3.4 hours. The apparent volume of distribution
of diltiazem is approximately 305 L. Diltiazem is extensively metabolized
in the liver with a systemic clearance of approximately 65 L/h. After
constant rate intravenous infusion to healthy male volunteers, diltiazem exhibits
nonlinear pharmacokinetics over an infusion range of 4.8 to 13.2 mg/h for
24 hours. Over this infusion range, as the dose is increased, systemic clearance
decreases from 64 to 48 L/h while the plasma elimination half-life increases
from 4.1 to 4.9 hours. The apparent volume of distribution remains unchanged
(360 to 391 L). In patients with atrial fibrillation or atrial flutter, diltiazem
systemic clearance has been found to be decreased compared to healthy volunteers.
In patients administered bolus doses ranging from 2.5 mg to 38.5 mg,systemic
clearance averaged 36 L/h. In patients administered continuous infusions at
10 mg/h or 15 mg/h for 24 hours, diltiazem systemic clearance averaged 42
L/h and 31 L/h, respectively. Based on the results of
pharmacokinetic studies in healthy volunteers administered different oral diltiazem hydrochloride formulations,
constant rate intravenous infusions of diltiazem hydrochloride at 3, 5, 7,
and 11 mg/h are predicted to produce steady-state plasma diltiazem concentrations
equivalent to 120-, 180-, 240-, and 360-mg total daily oral doses of diltiazem
hydrochloride tablets or diltiazem hydrochloride extended-release capsules. After
oral administration, diltiazem undergoes extensive metabolism in man by deacetylation,
N-demethylation, and O-demethylation via cytochrome P-450 (oxidative metabolism)
in addition to conjugation. Metabolites N-monodesmethyldiltiazem, desacetyldiltiazem,
desacetyl-N-monodesmethyldiltiazem, desacetyl-O-desmethyldiltiazem, and desacetyl-N,
O-desmethyldiltiazem have been identified in human urine. Following oral administration,
2% to 4% of the unchanged diltiazem appears in the urine. Drugs which induce
or inhibit hepatic microsomal enzymes may alter diltiazem disposition. Following
single intravenous injection of diltiazem, however, plasma concentrations
of N-monodesmethyldiltiazem and desacetyldiltiazem, two principal metabolites
found in plasma after oral administration, are typically not detected. These
metabolites are observed, however, following 24 hour constant rate intravenous
infusion. Total radioactivity measurement following short IV administration
in healthy volunteers suggests the presence of other unidentified metabolites
which attain higher concentrations than those of diltiazem and are more slowly
eliminated; half-life of total radioactivity is about 20 hours compared to
2 to 5 hours for diltiazem. Diltiazem hydrochloride
is 70% to 80% bound to plasma proteins. In vitrostudies suggest alpha���acid glycoprotein binds
approximately 40% of the drug at clinically significant concentrations. Albumin
appears to bind approximately 30% of the drug, while other constituents bind
the remaining bound fraction. Competitive in
vitro ligand binding studies have shown that diltiazem binding is
not altered by therapeutic concentrations of digoxin, phenytoin, hydrochlorothiazide,
indomethacin, phenylbutazone, propranolol, salicylic acid, tolbutamide, or
warfarin. Renal insufficiency, or even end-stage renal
disease, does not appear to influence diltiazem disposition following oral administration. Liver cirrhosis was
shown to reduce diltiazem's apparent oralclearance and prolong its half-life.
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Diltiazem hydrochloride injection is contraindicated in:
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Diltiazem Hydrochloride for Injection is supplied in single-dose
containers as follows: PRODUCT IS TO BE STORED AT 20 TO 25��C (68 TO 77��F).
[SEE USP CONTROLLED ROOM TEMPERATURE.] DO NOT FREEZE. RECONSTITUTED MATERIAL
IS STABLE FOR 24 HOURS AT CONTROLLED ROOM TEMPERATURE OR REFRIGERATED 2 to
8��C (36 to 46��F). SINGLE-USE VIAL. Rev:
June, 2006 ��Hospira 2006 EN-1222 Printed in USA HOSPIRA, INC., LAKE FOREST, IL 60045 USA
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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.<br/>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. 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 3-4 fold and Cby 2-fold, compared to placebo.
The elimination half-life of midazolam and triazolam also increased (1.5-2.5
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. Intravenous diltiazem has been administered
to patients on chronic oral beta-blocker therapy. The combination of the two
drugs was generally well tolerated without serious adverse effects. If intravenous
diltiazem is administered to patients receiving chronic oral beta-blocker
therapy, the possibility for bradycardia, AV block, and/or depression of contractility
should be considered (see CONTRAINDICATIONS). Oral administration
of diltiazem 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. Buspirone. In nine healthy subjects, diltiazem
significantly increased the mean buspirone AUC 5.5 fold and C4.1
fold compared to placebo. The Tand Tof 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 co-administration,
and should be based on clinical assessment. Carbamazepine. Concomitant administration of oral diltiazem with carbamazepine has been
reported to result in elevated plasma levels of carbamazepine (by 40 to 72%),
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. 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 dose ranging from 15% to 48% was necessary to
maintain cyclosporine trough 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 diltiazemtherapy is initiated, adjusted or discontinued. The
effect of cyclosporine on diltiazem plasma concentrations has not been evaluated. Digitalis. Intravenous diltiazem has been administered
to patients receiving either intravenous or oral digitalis therapy. The combination
of the two drugs was well tolerated without serious adverse effects. However,
since both drugs affect AV nodal conduction, patients should be monitored
for excessive slowing of the heart rate and/or AV block. Lovastatin. In a ten-subject study, coadministration
of diltiazem (120 mg bid, diltiazem SR) with lovastatin resulted in a 3-4
times increase in mean lovastatin AUC and Cversus lovastatin
alone; no change in pravastatin AUC and Cwas observed during
diltiazem coadministration. Diltiazem plasma levels were not significantly
affected by lovastatin or pravastatin. Quinidine.Diltiazem significantly increases the AUCof
quinidine by 51%, Tby 36% and decreases its CLby
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.<br/>Carcinogenesis, Mutagenesis, 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 or in
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.<br/>Pregnancy:: Teratogenic Effects-Pregnancy Category C Reproduction
studies have been conducted in mice, rats, and rabbits. Administration of
oral 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 oral antianginal
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.<br/>Nursing Mothers: Diltiazem is excreted in human milk. One report with oral
diltiazem 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.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been
established.<br/>Geriatric 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. Atrial fibrillation
or atrial flutter. In clinical studies with Diltiazem Injectable
(diltiazem HCl injection) for AF/Fl, 135 of 257 patients were over 65 years
of age. No overall differences in safety or effectiveness were observed between
these patients and younger patients, and other reported clinical experience
has not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled
out. In subgroup analysis of double-blind and open-label trials following
first-dose response, 116 patients over 65 years of age had a response rate
of 84%. One hundred two (102) patients<65 had a response rate of 78%.
In subgroup analysis following a two-dose procedure in double-blind and open-label
studies, 104 patients over 65 years of age and 95 patients<65 both had
a 95% response rate. Paroxysmal
supraventricular tachycardia. Clinical studies of Diltiazem Injectable
for PSVT did not include sufficient numbers of patients aged 65 and over to
determine whether they respond differently from younger patients. Other reported
clinical experience has not identified differences in responsesbetween 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. Diltiazem
hydrochloride is extensively metabolized by the liver and excreted by the
kidneys and in bile. The risk of toxic reactions to this drug may be greater
in patients with impaired renal or hepatic function. Because elderly patients
are more likely to have decreased renal function, care should be taken in
dose selection, and it may be useful to monitor renal function. As with all
drugs, care should be exercised when treating patients with multiple medications.
(See PRECAUTIONS,
General and Drug Interactions.)
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Overdosage experience is limited. In the event of overdosage
or an exaggerated response, appropriate supportive measures should be employed.
The following measures may be considered: Bradycardia:Administer atropine (0.6 to 1 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 levarterenol bitartrate). 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 10-20 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. Actual
treatment and dosage should depend on the severity of the clinical situation
and the judgment and experience of the treating physician. 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. The intravenous LD's
in mice and rats were 60 and 38 mg/kg, respectively. The toxic dose in man
is not known.
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Diltiazem Hydrochloride
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Diltiazem Hydrochloride (Powder, For Solution)
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The following adverse reaction rates are based on the use
of diltiazem hydrochloride in over 400 domestic clinical trial patients with
atrial fibrillation/flutter or PSVT under double-blind or open-label conditions.
Worldwide experience in over 1,300 patients was similar. Adverse
events reported in controlled and uncontrolled clinical trials were generally
mild and transient. Hypotension was the most commonly reported adverse event
during clinical trials. Asymptomatic hypotension occurred in 4.3% of patients.
Symptomatic hypotension occurred in 3.2% of patients. When treatment for hypotension
was required, it generally consisted of administration of saline or placing
the patient in the Trendelenburg position. Other events reported in at least
1% of the diltiazem-treated patients were injectionsite reactions (e.g.,
itching, burning) - 3.9%, vasodilation (flushing) - 1.7%, and arrhythmia (junctional
rhythm or isorhythmic dissociation) - 1%. In addition,
the following events were reported infrequently (less than 1%): Cardiovascular: Asystole, atrial flutter, AV block
first degree, AV block second degree, bradycardia, chest pain, congestive
heart failure, sinus pause, sinus node dysfunction, syncope, ventricular arrhythmia,
ventricular fibrillation, ventricular tachycardia. Dermatologic: Pruritus, sweating. Gastrointestinal: Constipation, elevated SGOT or
alkaline phosphatase, nausea, vomiting. Nervous
System: Dizziness, paresthesia. Other:Amblyopia, asthenia, dry mouth, dyspnea, edema, headache, hyperuricemia. Although
not observed in clinical trials with diltiazem hydrochloride injection, the
following events associated with oral diltiazem may occur: Cardiovascular: AV block (third degree), bundle
branch block, ECG abnormality, palpitations, syncope, tachycardia, ventricular
extrasystoles. Dermatologic:Alopecia, erythema multiforme (including Stevens-Johnson syndrome,
toxic epidermal necrolysis), exfoliative dermatitis, leukocytoclastic vasculitis,
petechiae, photosensitivity, purpura, rash, urticaria. Gastrointestinal: Anorexia, diarrhea, dysgeusia,
dyspepsia, mild elevations of SGPT and LDH, thirst, weight increase. Nervous System: Abnormal dreams, amnesia, depression,
extrapyramidal symptoms, gait abnormality, hallucinations, insomnia, nervousness,
personality change, somnolence, tremor. Other:Allergic reactions, angioedema (including facial or periorbital
edema), CPK elevation, epistaxis, eye irritation, gingival hyperplasia, hemolytic
anemia, hyperglycemia, impotence, increased bleeding time, leukopenia, muscle
cramps, myopathy, nasal congestion, nocturia, osteoarticular pain, polyuria,
retinopathy, sexual difficulties, thrombocytopenia, tinnitus. Events
such as myocardial infarction have been observed which are not readily distinguishable
from the natural history of the disease for the patient.
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NOTE: This drug product
is not for direct bolus injection. Text referring to direct bolus injection
is provided for information purposes only. Diltiazem Hydrochloride for Injection
is indicated for the following: The use of diltiazem hydrochloride 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 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.
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| dailymed-instance:represent... | |
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| dailymed-instance:name |
Diltiazem Hydrochloride
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