DILTIAZEM HYDROCHLORIDE (Page 4 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 CLINICAL STUDIES

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.

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 hydrochloride. These antiarrhythmic agents were intravenous or oral digoxin, Class 1 antiarrhythmics (e.g., quinidine, procainamide), calcium channel blockers, and oral beta-blockers.

16 HOW SUPPLIED/STORAGE AND HANDLING

Diltiazem Hydrochloride Injection is supplied as a sterile, unpreserved, colorless solution in a single-dose polymeric bag containing 1 mg/mL of diltiazem as either a 125 mg of diltiazem in 125 mL of solution (51754-3000-1) or 250 mg diltiazem in 250 mL (51754-3500-1) sealed with a Twist Off port and oversealed in an aluminum pouch.

Discard any unused portion.

Store under refrigeration at 2°C to 8°C (36°F to 46°F). The single-dose bags in their original pouches are stable for up to one month at room temperature without significant loss of potency. The bag and port is not made with natural rubber latex, PVC, or DEHP.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL-125 mL IV Bag Label

125 ml bag label
(click image for full-size original)

NDC 51754-3000-1 125 mL

USE IMMEDIATELY ONCE REMOVED FROM THE OVERWRAP

Diltiazem Hydrochloride in 5% Dextrose Injection

125 mg per 125 mL (1 mg per mL)

For intravenous use only Single-Dose Container-Discard Unused Portion

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL-125 mL Overwrap Label

125 ml overwrap
(click image for full-size original)

TO OPEN-TEAR AT NOTCH 125 mL Single-Dose Container

LEAVE BAG IN OVERWRAP UNTIL USE Discard Unused Portion

Diltiazem Hydrochloride in 5% Dextrose Injection

125 mg per 125 mL (1 mg per mL)

For intravenous use only

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL-250 mL IV Bag Label

250 ml bag label
(click image for full-size original)

NDC 51754-3500-1 250 mL

USE IMMEDIATELY ONCE REMOVED FROM THE OVERWRAP

Diltiazem Hydrochloride in 5% Dextrose Injection

250 mg per 250 mL (1 mg per mL)

For intravenous use only Single-Dose Container-Discard Unused Portion

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL-250 mL Overwrap Label

250 ml overwrap
(click image for full-size original)

TO OPEN-TEAR AT NOTCH 250 mL Single-Dose Container

LEAVE BAG IN OVERWRAP UNTIL USE Discard Unused Portion

Diltiazem Hydrochloride in 5% Dextrose Injection

250 mg per 250 mL (1 mg per mL)

For intravenous use only

DILTIAZEM HYDROCHLORIDE
diltiazem hydrochloride injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:51754-3000
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DILTIAZEM HYDROCHLORIDE (DILTIAZEM) DILTIAZEM HYDROCHLORIDE 1 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
ANHYDROUS DEXTROSE
CITRIC ACID MONOHYDRATE
TRISODIUM CITRATE DIHYDRATE
WATER
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:51754-3000-3 10 BAG in 1 CARTON contains a BAG
1 125 mL in 1 BAG This package is contained within the CARTON (51754-3000-3)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA215252 11/30/2021
DILTIAZEM HYDROCHLORIDE
diltiazem hydrochloride injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:51754-3500
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DILTIAZEM HYDROCHLORIDE (DILTIAZEM) DILTIAZEM HYDROCHLORIDE 1 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
ANHYDROUS DEXTROSE
CITRIC ACID MONOHYDRATE
TRISODIUM CITRATE DIHYDRATE
WATER
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:51754-3500-3 10 BAG in 1 CARTON contains a BAG
1 250 mL in 1 BAG This package is contained within the CARTON (51754-3500-3)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA215252 11/30/2021
Labeler — Exela Pharma Sciences,LLC (831274399)
Establishment
Name Address ID/FEI Operations
Exela Pharma Sceinces, LLC 831274399 ANALYSIS (51754-3000), ANALYSIS (51754-3500), MANUFACTURE (51754-3000), MANUFACTURE (51754-3500), LABEL (51754-3000), LABEL (51754-3500), PACK (51754-3000), PACK (51754-3500)

Revised: 11/2021 Exela Pharma Sciences,LLC

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