Diltiazem Hydrochloride (Page 4 of 6)

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 hydrochloride 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 hydrochloride injection 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 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.

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.)

ADVERSE REACTIONS

The following adverse reaction rates are based on the use of diltiazem hydrochloride injection 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 injection site 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: A cute generalized exanthematous pustulosis, 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, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), 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.

OVERDOSAGE

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 norepinephrine).

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.

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 LD₅₀ ‘s in mice and rats were 60 and 38 mg/kg, respectively. The toxic dose in man is not known.

DOSAGE AND ADMINISTRATION

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 injection or diltiazem hydrochloride for injection may be administered. (For reconstitution of diltiazem hydrochloride for injection, see instructions contained within packaging.) 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 or diltiazem hydrochloride for injection. The recommended initial infusion rate of diltiazem hydrochloride injection or diltiazem hydrochloride for 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.