Diltiazem Hydrochloride in Sodium Chloride Injection is indicated in adults for the temporary control of rapid ventricular rate in atrial fibrillation or atrial flutter.

Diltiazem Hydrochloride in Sodium Chloride Injection is indicated in adults for rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm.

Administer intravenous diltiazem in a setting with continuous monitoring of the ECG and frequent measurement of blood pressure. A defibrillator and emergency equipment should be readily available.

Diltiazem Hydrochloride in Sodium Chloride Injection is a ready to administer product that requires no further dilution prior to infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

The initial dose of diltiazem hydrochloride should be 0.25 mg/kg actual body weight 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 dose of diltiazem hydrochloride 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.

Immediately following bolus, the recommended initial infusion rate of diltiazem hydrochloride is 5 mg/hour. Adjust the infusion rate in 5 mg/hour increments up to a maximum of 15 mg/hour as needed to achieve satisfactory rate control. Infusions longer than 24 hours have not been studied. Patients should generally be transitioned to other antiarrhythmic agents within 24 hours [see Clinical Studies (14)].

Do not mix diltiazem hydrochloride with any other drugs in the same container. If possible, use a dedicated line for diltiazem hydrochloride.

Diltiazem hydrochloride has demonstrated physical incompatibilities with 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.

Injection: Clear, colorless solution in a single-dose bag for intravenous use.

{ "type": "p", "children": [], "text": "Injection: Clear, colorless solution in a single-dose bag for intravenous use." }

100 mg per 100 mL (1 mg/mL)

{ "type": "p", "children": [], "text": "100 mg per 100 mL (1 mg/mL)" }

250 mg per 250 mL (1 mg/mL)

{ "type": "p", "children": [], "text": "250 mg per 250 mL (1 mg/mL) " }

Diltiazem Hydrochloride in Sodium Chloride Injection is contraindicated in the following situations:

{ "type": "p", "children": [], "text": "Diltiazem Hydrochloride in Sodium Chloride Injection is contraindicated in the following situations: " }

{ "type": "", "children": [], "text": "" }

Diltiazem may cause ventricular fibrillation if given to patients in atrial fibrillation or atrial flutter associated with an accessory bypass tract such as in WPW syndrome. Distinguish atrial fibrillation with aberrancy (bundle branch block) from pre-excited atrial fibrillation prior to diltiazem administration [see Contraindications (4)].

Diltiazem may cause hemodynamic deterioration and ventricular fibrillation if administered to patients with wide complex tachycardia of ventricular origin. Distinguish wide complex QRS tachycardia of supraventricular origin from that of ventricular origin prior to diltiazem administration [see Contraindications (4)].

Diltiazem prolongs AV nodal conduction and refractoriness that may cause 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 (7)]. If high-degree AV block occurs in sinus rhythm, discontinue diltiazem and institute appropriate supportive measures [see Overdosage (10)].

Diltiazem is a negative inotrope and can cause decreased systolic function and heart failure. Do not initiate in patients with acute decompensated heart failure or cardiogenic shock. If heart failure develops during diltiazem treatment, discontinue treatment and treat heart failure appropriately.

Diltiazem can cause symptomatic hypotension. Patients with low blood pressure at baseline and those on concomitant medications that decrease blood pressure, intravascular volume, or myocardial contractility are at increased risk for hypotension.

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.

{ "type": "p", "children": [], "text": "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. " }

Hypotension was the most commonly reported adverse event during clinical trials, with symptomatic hypotension occurring in 3.2% of patients. Other events reported in a 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%.

{ "type": "p", "children": [], "text": "Hypotension was the most commonly reported adverse event during clinical trials, with symptomatic hypotension occurring in 3.2% of patients. Other events reported in a 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%):

{ "type": "p", "children": [], "text": "In addition, the following events were reported infrequently (less than 1%): " }

Gastrointestinal - Constipation, elevated SGOT or alkaline phosphatase, nausea, vomiting

{ "type": "p", "children": [], "text": "\nGastrointestinal - Constipation, elevated SGOT or alkaline phosphatase, nausea, vomiting " }

Nervous System - Dizziness

{ "type": "p", "children": [], "text": "\nNervous System - Dizziness " }

Other - dyspnea, edema, headache,

{ "type": "p", "children": [], "text": "\nOther - dyspnea, edema, headache, " }

Although not observed in clinical trials with diltiazem hydrochloride injection, the following events associated with oral diltiazem may occur:

{ "type": "p", "children": [], "text": "Although not observed in clinical trials with diltiazem hydrochloride injection, the following events associated with oral diltiazem may occur: " }

Dermatologic - Erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), exfoliative dermatitis, petechiae, photosensitivity, purpura, pruritus, rash, urticaria, acute generalized exanthematous pustulosis,

{ "type": "p", "children": [], "text": "\nDermatologic - Erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), exfoliative dermatitis, petechiae, photosensitivity, purpura, pruritus, rash, urticaria, acute generalized exanthematous pustulosis, " }

Gastrointestinal - Anorexia, dysgeusia, dyspepsia

{ "type": "p", "children": [], "text": "\nGastrointestinal - Anorexia, dysgeusia, dyspepsia " }

Other - Allergic reactions, angioedema (including facial or periorbital edema), gingival hyperplasia, hyperglycemia, impotence.

{ "type": "p", "children": [], "text": "\nOther - Allergic reactions, angioedema (including facial or periorbital edema), gingival hyperplasia, hyperglycemia, impotence." }

Table 1. Clinically Relevant Interactions with Diltiazem

{ "type": "p", "children": [], "text": "\nTable 1. Clinically Relevant Interactions with Diltiazem\n" }

<div class="scrollingtable"><table width="100%"> <col width="30%"/> <col width="35%"/> <col width="35%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Drug/Substance Class or Name</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Clinical implication</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Prevention/Management</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Agents Known to decrease peripheral resistance, cardiac contractility or conduction</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Increased risk of bradycardia, AV block, and heart failure. </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Monitor.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Beta-blockers</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Increased risk of bradycardia, AV block, and depression of contractility.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Beta-blocker may need to be decreased<span class="Italics"> [see Warnings and Precautions (5.1, 5.2)].</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Anesthetics</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Depressed cardiac contractility, conductivity, and automaticity as well as the vascular dilation. </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Monitor.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Clonidine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Increased risk of bradycardia. </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Monitor<span class="Italics">.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Drugs metabolized by Cytochrome P450 3A4</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Diltiazem is both a substrate and an inhibitor of the cytochrome P450 3A4 enzyme system. Concomitant use with diltiazem can increase exposure of drugs that are substrates of CYP450 3A4. </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Drugs that are substrates of CYP450 3A4 may require dose adjustment to maintain optimum therapeutic blood levels. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Benzodiazepines</p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="6" valign="middle"> <p class="First">Increased exposure likely.</p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="5" valign="middle"> <p class="First">Monitor.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Buspirone</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Carbamazepine</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cyclosporine</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Quinidine</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Ranolazine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Limit ranolazine to 500 mg twice daily. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Statins</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">When possible, use a non-CYP3A4-metabolized statin with diltiazem.</p> <p>Limit daily dose of simvastatin to 10 mg and diltiazem to 240 mg <span class="Italics">[see Clinical Pharmacology (12.3)].</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ivabradine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">May exacerbate bradycardia and conduction disturbances.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Avoid concomitant use <span class="Italics">[see Clinical Pharmacology (12.3)]</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Effect of other drugs on Diltiazem</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Cytochrome P450 3A4 Inhibitors/ Inducers</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Diltiazem is a substrate of the cytochrome P450 3A4 enzyme and inhibitors/inducers may change the pharmacological effect of diltiazem</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Monitor.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Strong or moderate CYP 3A inhibitors <span class="Sup">a</span> </p> <p>Examples <span class="Sup">b</span>: Ketoconazole, itraconazole, cimetidine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with strong or moderate inhibitors of CYP3A4.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">An adjustment in the diltiazem dose may be warranted </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">CYP inducers</p> <p>Examples <span class="Sup">b</span>: Rifampin, carbamazepine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">CYP3A inducers can lower the plasma levels of diltiazem.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered <span class="Italics">[see Clinical Pharmacology (12.3)].</span> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"30%\"/>\n<col width=\"35%\"/>\n<col width=\"35%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Drug/Substance Class or Name</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Clinical implication</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Prevention/Management</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Agents Known to decrease peripheral resistance, cardiac contractility or conduction</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Increased risk of bradycardia, AV block, and heart failure. </p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Monitor.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Beta-blockers</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Increased risk of bradycardia, AV block, and depression of contractility.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Beta-blocker may need to be decreased<span class=\"Italics\"> [see Warnings and Precautions (5.1, 5.2)].</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Anesthetics</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Depressed cardiac contractility, conductivity, and automaticity as well as the vascular dilation. </p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Monitor.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Clonidine</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Increased risk of bradycardia. </p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Monitor<span class=\"Italics\">.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Drugs metabolized by Cytochrome P450 3A4</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Diltiazem is both a substrate and an inhibitor of the cytochrome P450 3A4 enzyme system. Concomitant use with diltiazem can increase exposure of drugs that are substrates of CYP450 3A4. </p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Drugs that are substrates of CYP450 3A4 may require dose adjustment to maintain optimum therapeutic blood levels. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Benzodiazepines</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" rowspan=\"6\" valign=\"middle\">\n<p class=\"First\">Increased exposure likely.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" rowspan=\"5\" valign=\"middle\">\n<p class=\"First\">Monitor.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Buspirone</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Carbamazepine</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Cyclosporine</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Quinidine</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Ranolazine</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Limit ranolazine to 500 mg twice daily. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Statins</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Increased risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">When possible, use a non-CYP3A4-metabolized statin with diltiazem.</p>\n<p>Limit daily dose of simvastatin to 10 mg and diltiazem to 240 mg <span class=\"Italics\">[see Clinical Pharmacology (12.3)].</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Ivabradine</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">May exacerbate bradycardia and conduction disturbances.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Avoid concomitant use <span class=\"Italics\">[see Clinical Pharmacology (12.3)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Effect of other drugs on Diltiazem</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Cytochrome P450 3A4 Inhibitors/ Inducers</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Diltiazem is a substrate of the cytochrome P450 3A4 enzyme and inhibitors/inducers may change the pharmacological effect of diltiazem</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Monitor.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Strong or moderate CYP 3A inhibitors <span class=\"Sup\">a</span>\n</p>\n<p>Examples <span class=\"Sup\">b</span>: Ketoconazole, itraconazole, cimetidine</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with strong or moderate inhibitors of CYP3A4.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">An adjustment in the diltiazem dose may be warranted </p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">CYP inducers</p>\n<p>Examples <span class=\"Sup\">b</span>: Rifampin, carbamazepine</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">CYP3A inducers can lower the plasma levels of diltiazem.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered <span class=\"Italics\">[see Clinical Pharmacology (12.3)].</span>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

{ "type": "", "children": [], "text": "" }

Risk Summary

The available data from the published literature over decades of use with diltiazem during pregnancy have not identified a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, decreased embryo and fetal survival rates, and skeletal abnormalities have been observed at oral doses five to ten times the human oral antianginal therapeutic dose, and reduction in pup weights was also observed. At 20 times the human oral antianginal therapeutic dose, an increase in stillbirths was observed (see Data).

The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

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 human 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 therapeutic dose or greater.

Risk Summary

Published literature reports the presence of diltiazem in human milk. One report with oral diltiazem suggests that concentrations in breast milk may approximate serum levels. There are no data on the effects of diltiazem on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Diltiazem Hydrochloride Injection and any potential adverse effects on the breastfed child from Diltiazem Hydrochloride Injection or from the underlying maternal condition.

Safety and effectiveness in pediatric patients have not been established.

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.

Overdosage experience is limited. In the event of overdosage or an exaggerated response, appropriate supportive measures should be employed.

{ "type": "p", "children": [], "text": "Overdosage experience is limited. In the event of overdosage or an exaggerated response, appropriate supportive measures should be employed. " }

Diltiazem does not appear to be removed by peritoneal or hemodialysis. Limited data suggest that plasmapheresis may hasten diltiazem elimination following overdose.

{ "type": "p", "children": [], "text": "Diltiazem does not appear to be removed by peritoneal or hemodialysis. Limited data suggest that plasmapheresis 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 humans is not known.

{ "type": "p", "children": [], "text": "The intravenous LD50's in mice and rats were 60 and 38 mg/kg, respectively. The toxic dose in humans is not known. " }

Diltiazem Hydrochloride in Sodium Chloride Injection is a non-dihydropyridine calcium channel-blocker. Diltiazem hydrochloride is 1,5-benzothiazepin-4(5H)one,3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2, 3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride, (+)-cis- with the molecular weight of 450.98 and structural formula:

{ "type": "p", "children": [], "text": "Diltiazem Hydrochloride in Sodium Chloride Injection is a non-dihydropyridine calcium channel-blocker. Diltiazem hydrochloride is 1,5-benzothiazepin-4(5H)one,3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2, 3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride, (+)-cis- with the molecular weight of 450.98 and structural formula:" }

Molecular formula: C22H26N204S.HCl

{ "type": "p", "children": [], "text": "Molecular formula: C22H26N204S.HCl " }

Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste soluble in water, methanol, and chloroform.

{ "type": "p", "children": [], "text": "Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste soluble in water, methanol, and chloroform. " }

Diltiazem Hydrochloride in Sodium Chloride Injection is a clear, colorless, sterile, nonpyrogenic, isotonic solution for intravenous use only. It is packaged in single-dose bags containing 100 mg/100 mL and 250 mg/250 mL. Each mL contains: 1 mg diltiazem hydrochloride, USP (equivalent to 0.92 mg diltiazem), 0.15 mg citric acid monohydrate, USP, 7.2 mg sodium chloride, USP, 0.13 mg sodium citrate dihydrate, USP, 10 mg sorbitol, NF, and water for injection, USP. Hydrochloric acid, NF and/or sodium hydroxide are added as needed to adjust pH to 4.5 - 5.5.

{ "type": "p", "children": [], "text": "Diltiazem Hydrochloride in Sodium Chloride Injection is a clear, colorless, sterile, nonpyrogenic, isotonic solution for intravenous use only. It is packaged in single-dose bags containing 100 mg/100 mL and 250 mg/250 mL. Each mL contains: 1 mg diltiazem hydrochloride, USP (equivalent to 0.92 mg diltiazem), 0.15 mg citric acid monohydrate, USP, 7.2 mg sodium chloride, USP, 0.13 mg sodium citrate dihydrate, USP, 10 mg sorbitol, NF, and water for injection, USP. Hydrochloric acid, NF and/or sodium hydroxide are added as needed to adjust pH to 4.5 - 5.5." }

The therapeutic effects of diltiazem are believed to be related to inhibiting influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.

Paroxysmal Supraventricular Tachycardia: Diltiazem slows AV nodal conduction time and prolongs 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.

Atrial Fibrillation or Atrial Flutter: 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.

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 effect on tissues in the heart that are fast sodium channel dependent, e.g., His-Purkinje tissue, atrial and ventricular muscle, and extra nodal 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.

Intravenous diltiazem hydrochloride 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. PR in healthy volunteers and HR in patients with atrial fibrillation and atrial flutter are dependent on plasma level of diltiazem. Based on this relationship, the mean plasma diltiazem concentration required to produce a 20%, 30% and 40% decrease in heart rate was determined to be 80 ng/mL, 130 ng/mL and 300 ng/mL, respectively.

In patients with cardiovascular disease, diltiazem hydrochloride 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.

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 and diltiazem hydrochloride extended-release capsules.

Distribution

The volume of distribution of diltiazem is approximately 305 L. Diltiazem is 70% to 80% bound to plasma proteins. In vitro studies suggest alpha1-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 hydrochloride binding is not altered by therapeutic concentrations of digoxin, phenytoin, hydrochlorothiazide, indomethacin, phenylbutazone, propranolol, salicylic acid, tolbutamide, or warfarin.

Metabolism and Excretion

Diltiazem is extensively metabolized in the liver. 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. These metabolites are also observed following 24-hour constant rate intravenous infusion.

The systemic clearance of diltiazem has been found to be decreased in patients with atrial fibrillation or atrial flutter, compared to healthy volunteers. In patients administered continuous infusions at 10 mg/h or 15 mg/h for 24 h, diltiazem systemic clearance averaged 42 L/h and 31 L/h, respectively. The plasma elimination half-life is approximately 3.4 h. 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 h compared to 2 to 5 h for diltiazem.

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 h. 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 h. The volume of distribution remains unchanged (360 to 391 L).

Specific Populations

Renal insufficiency, or even end-stage renal disease, does not appear to influence diltiazem disposition following oral administration. Liver cirrhosis reduces diltiazem's apparent clearance and prolong its half-life.

Drug Interaction Studies

Effect of Diltiazem on Other Drugs:

Agents known to Decrease Peripheral Resistance, Cardiac Contractility and Conduction

Beta-blockers: Controlled and uncontrolled domestic studies suggest that concomitant use of diltiazem and beta-blockers is usually well tolerated, but available data are not sufficient to predict the effects of concomitant treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities. Administration of diltiazem concomitantly 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 [see Warnings and Precautions (5.2, 5.3)].

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.

Ivabradine: Coadministration with diltiazem resulted in approximately 3-fold the AUC and Cmax of ivabradine and 20-60% increase in the active metabolite (S18982) exposure [see Drug Interactions (7)].

CYP3A4 Substrates

Benzodiazepines: With diltiazem, the AUC of midazolam and triazolam is 3- to 4-fold and the Cmax is 2-fold what they are alone. The elimination half-life of midazolam and triazolam also increased by 50-150% during coadministration with diltiazem [see Drug Interactions (7)].

Buspirone: With diltiazem, the mean buspirone AUC was about 5.5-fold and Cmax was about 4.1-fold what they are alone. The t1/2 and Tmax of buspirone were not affected by diltiazem [see Drug Interactions (7)].

Carbamazepine: Concomitant administration of diltiazem with carbamazepine was reported to result in elevated serum levels of carbamazepine (40% to 72% increase), resulting in toxicity in some cases [see Drug Interactions (7)].

Cyclosporine: 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 diltiazem therapy is initiated, adjusted, or discontinued. The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated [see Drug Interactions (7)].

Quinidine: Diltiazem increases the AUC of quinidine by 51%, elimination half-life by 36%, and decreases its oral clearance by 33% [see Drug Interactions (7)].

Ranolazine: On coadministration with diltiazem 180 to 360 mg daily, the plasma levels of ranolazine are 2.2-to 2.8-fold what they are alone. Diltiazem plasma levels are not affected by ranolazine [see Drug Interactions (7)].

Statins: Diltiazem has been shown to increase the AUC of some statins. The risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4 may be increased with concomitant use of diltiazem [see Drug Interactions (7)].

Coadministration of a simvastatin with 120 mg BID diltiazem SR resulted in 5 times the mean simvastatin AUC versus simvastatin alone. Higher doses of diltiazem are likely to be worse.

Coadministration of a lovastatin with 120 mg BID diltiazem SR resulted in a 3 to 4 times the mean lovastatin AUC and Cmax versus lovastatin alone. In the same study, there was no significant change in AUC and Cmax of 20 mg single dose pravastatin during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

Effect of Other Drugs on Diltiazem:

CYP3A4 Inhibitors and Inducers

Cimetidine and Ranitidine: Coadministration with cimetidine increased Cmax of diltiazem by 58% and AUC by 53%. Ranitidine produced smaller, non-significant increases. The effect may be mediated by cimetidine's known inhibition of hepatic CYP3A, the enzyme system responsible for the first-pass metabolism of diltiazem [see Drug Interactions (7)].

Rifampin: Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels [see Drug Interactions (7)].

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.

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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. " }

Diltiazem Hydrochloride in Sodium Chloride Injection is supplied as a clear, colorless solution in a single-dose bag with an aluminum overwrap available as:

{ "type": "p", "children": [], "text": "Diltiazem Hydrochloride in Sodium Chloride Injection is supplied as a clear, colorless solution in a single-dose bag with an aluminum overwrap available as:" }

<div class="scrollingtable"><table class="Noautorules" width="540pt"> <col width="31%"/> <col width="21%"/> <col width="25%"/> <col width="23%"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Total Strength per Total Volume</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Strength per mL</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Carton of 10 single-dose bags NDC</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Bag and Overwrap NDC</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">100 mg per 100 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">44567-662-10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">44567-662-01</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">250 mg per 250 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">44567-663-10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">44567-663-01</p> </td> </tr> </tbody> </table></div>

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Discard any unused portion.

{ "type": "p", "children": [], "text": "Discard any unused portion." }

Store under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. The single-dose bags in their original overwraps may be stored for up to one month at 20°C to 25°C [68°F to 77°F], [See USP Controlled Room Temperature]. The bag and port are not made with natural rubber latex, PVC, or DEHP.

{ "type": "p", "children": [], "text": "Store under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. The single-dose bags in their original overwraps may be stored for up to one month at 20°C to 25°C [68°F to 77°F], [See USP Controlled Room Temperature]. The bag and port are not made with natural rubber latex, PVC, or DEHP." }

Product should be used within 28 days of removal from aluminum overwrap.

{ "type": "p", "children": [], "text": "Product should be used within 28 days of removal from aluminum overwrap." }

Manufactured for: WG Critical Care, LLC Paramus, NJ 07652

{ "type": "p", "children": [], "text": "Manufactured for:\nWG Critical Care, LLC\nParamus, NJ 07652" }

Made in Switzerland

{ "type": "p", "children": [], "text": "Made in Switzerland" }

NDC 44567-662-01Diltiazem Hydrochloridein 0.72% Sodium Chloride Injection100 mg per 100 mL(1 mg per mL)

{ "type": "p", "children": [], "text": "NDC 44567-662-01Diltiazem Hydrochloridein 0.72% Sodium Chloride Injection100 mg per 100 mL(1 mg per mL)" }

NDC 44567-663-01Diltiazem Hydrochloridein 0.72% Sodium Chloride Injection250 mg per 250 mL(1 mg per mL)

{ "type": "p", "children": [], "text": "NDC 44567-663-01Diltiazem Hydrochloridein 0.72% Sodium Chloride Injection250 mg per 250 mL(1 mg per mL)" }

CARDIZEM LA is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mm Hg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

CARDIZEM LA may be used alone or in combination with other antihypertensive medications.

CARDIZEM LA is indicated to improve exercise tolerance in patients with chronic stable angina.

Initiate dosing at 180 to 240 mg once daily, although some patients may respond to lower doses. Titrate according to blood pressure to a maximum of 540 mg daily. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy.

Initiate dosing at 180 mg once daily and increase dose at intervals of 7 to 14 days if adequate response is not obtained, to a maximum of 360 mg.

Patients controlled on diltiazem alone or in combination with other medications may be switched to CARDIZEM LA once a day at the nearest equivalent total daily dose. Higher doses of CARDIZEM LA may be needed in some patients based on clinical response.

Extended-release tablets with 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, or 420 mg diltiazem hydrochloride per tablet. CARDIZEM LA Tablets are supplied as capsule shaped, white film-coated tablets, debossed with “B” on one side and the diltiazem content (mg) on the other.

{ "type": "p", "children": [], "text": "Extended-release tablets with 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, or 420 mg diltiazem hydrochloride per tablet. CARDIZEM LA Tablets are supplied as capsule shaped, white film-coated tablets, debossed with “B” on one side and the diltiazem content (mg) on the other." }

CARDIZEM LA is contraindicated in:

{ "type": "p", "children": [], "text": "CARDIZEM LA is contraindicated in:" }

{ "type": "ul", "children": [ "Patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker.", "Patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker.", "Patients with hypotension (less than 90 mm Hg systolic).", "Patients who have demonstrated hypersensitivity to the drug.", "Patients with acute myocardial infarction and pulmonary." ], "text": "" }

CARDIZEM LA may cause abnormally slow heart rates or second- or third-degree AV block. Patients with sick sinus syndrome are at increased risk of bradycardia. 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 ( 6)] . Monitor for effects on heart rate and cardiac conduction.

Worsening of heart failure has been reported in patients with impairment of ventricular function. Experience with the use of diltiazem in combination with beta-blockers in patients with impaired ventricular function is limited.

Significant elevations in liver enzymes such as alkaline phosphatase, LDH, AST (SGOT), ALT (SGPT) and signs of acute hepatic injury have been reported with diltiazem therapy. These reactions tended to occur early after therapy initiation (1 to 8 weeks) and have been reversible upon discontinuation of drug therapy. Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have also been observed. Such elevations were usually transient and frequently resolved even with continued diltiazem treatment.

Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme and/or exfoliative dermatitis have been reported.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

For the hypertension studies, the following table presents adverse reactions more common on diltiazem than on placebo (but excluding events with no plausible relationship to treatment), as reported in placebo-controlled hypertension trials in patients receiving a diltiazem hydrochloride extended-release formulation (once-a-day dosing) up to 540 mg.

<div class="scrollingtable"><table cellpadding="0.75pt" width="100%"> <col width="32%"/> <col width="23%"/> <col width="23%"/> <col width="23%"/> <thead> <tr class="First"> <th align="left" class="Lrule Toprule" valign="bottom"></th><th align="center" class="Botrule Lrule Toprule" valign="bottom"><span class="Bold">Placebo</span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"><span class="Bold">Diltiazem</span> <br/> <span class="Bold">hydrochloride</span> <br/> <span class="Bold">extended-release</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule" valign="bottom"><span class="Bold">Adverse Reactions</span> <br/> <span class="Bold">(MedDRA Term)</span></th><th align="center" class="Botrule Lrule" valign="bottom"><span class="Bold">n=120</span> <br/> <span class="Bold"># pts. (%)</span></th><th align="center" class="Botrule Lrule" valign="bottom"><span class="Bold">120-360 mg</span> <br/> <span class="Bold">n=501</span> <br/> <span class="Bold"># pts. (%)</span></th><th align="center" class="Botrule Lrule Rrule" valign="bottom"><span class="Bold">540 mg</span> <br/> <span class="Bold">n=123</span> <br/> <span class="Bold"># pts. (%)</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Lrule Toprule" valign="bottom"> <p class="First">Edema lower limb</p> </td><td align="center" class="Lrule Toprule" valign="bottom"> <p class="First">4 (3)</p> </td><td align="center" class="Lrule Toprule" valign="bottom"> <p class="First">24 (5)</p> </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> <p class="First">10 (8)</p> </td> </tr> <tr> <td class="Lrule" valign="bottom"> <p class="First">Sinus congestion</p> </td><td align="center" class="Lrule" valign="bottom"> <p class="First">0 (0)</p> </td><td align="center" class="Lrule" valign="bottom"> <p class="First">2 (1)</p> </td><td align="center" class="Lrule Rrule" valign="bottom"> <p class="First">2 (2)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule" valign="bottom"> <p class="First">Rash</p> </td><td align="center" class="Botrule Lrule" valign="bottom"> <p class="First">0 (0)</p> </td><td align="center" class="Botrule Lrule" valign="bottom"> <p class="First">3 (1)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">2 (2)</p> </td> </tr> </tbody> </table></div>

In the angina study, the adverse event profile of CARDIZEM LA was consistent with what has been previously described for CARDIZEM LA and other formulations of diltiazem HCl. The most frequent adverse effects experienced by CARDIZEM LA-treated patients were edema lower-limb (6.8%), dizziness (6.4%), fatigue (4.8%), bradycardia (3.6%), first-degree atrioventricular block (3.2%), and cough (2%).

In addition, the following events have been reported infrequently (less than 1%) in angina or hypertension trials:

Cardiovascular:Angina, bundle branch block, palpitations, syncope, tachycardia, ventricular extrasystoles [see Warnings and Precautions (5.1, 5.2)].

Nervous System:Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tinnitus, tremor.

Gastrointestinal:Anorexia, constipation, diarrhea, dry mouth, dysgeusia, dyspepsia, thirst, vomiting, weight increase.

Dermatological:Petechiae, photosensitivity, pruritus, urticaria [see Warnings and Precautions ( 5.4)].

Other:Amblyopia, CPK increase, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties.

The following adverse reactions have been identified during post -approval use of diltiazem. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.

The following post -marketing reactions have been reported infrequently in patients receiving diltiazem: acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema (including facial or periorbital edema), erythema multiforme, extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), purpura, retinopathy, myopathy, and thrombocytopenia.

In addition, events such as myocardial infarction have been observed which are not readily distinguishable from the natural history of the disease in these patients.

A number of well-documented cases of generalized rash, some characterized as leukocytoclastic vasculitis, have been reported.

Using other agents known to affect cardiac conduction or contractility with diltiazem may increase the risk of bradycardia, AV block, and heart failure [see Warnings and Precautions (5.1, 5.2)].

Ivabradine:Concurrent use of diltiazem increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid concomitant use of ivabradine and diltiazem.

Diltiazem is both a substrate and an inhibitor of the Pg-p and cytochrome P450 3A4 enzyme system which may affect exposure to diltiazem and concomitant drugs metabolized by those pathways. Patients with renal and/or hepatic impairment may be particularly at risk of exposure changes [see Clinical Pharmacology (12.3)].

Risk Summary

The available data from the published literature over decades of use with diltiazem during pregnancy have not identified a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies in rats and rabbits, administration of diltiazem to pregnant animals during organogenesis at oral doses approximately 1 and 4 times the Maximum Recommended Human Dose (MRHD) of CARDIZEM LA produced embryofetal deaths and increased incidence of skeletal abnormalities. An increased incidence of stillbirths was noted at diltiazem doses approximately 2 times the MRHD of CARDIZEM LA.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2- 4% and 15-20%, respectively.

Data

Animal Data

Embryofetal development studies have been conducted with diltiazem in rats and rabbits. Daily oral administration of diltiazem at 0, 17.5, 35 or 70 mg/kg to pregnant rabbits during organogenesis (gestational day 6 to 18) resulted in embryo-fetal lethality at 35 mg/kg/day (approximately 1 time the MRHD of CARDIZEM LA, on a mg/m 2basis) and higher, concurrent with maternal toxicity (reduced body weight gain). Daily oral administration of diltiazem at 0, 100, 200 and 400 mg/kg to pregnant rats during organogenesis (gestation day 9 to 14) resulted in embryo-fetal lethality at 200 mg/kg/day (approximately 4 times the MRHD of CARDIZEM LA, on a mg/m 2basis) and higher. These doses, in some studies, were reported to cause increased incidence of skeletal malformations (e.g. malformations of vertebral column) or variations. In an oral perinatal/postnatal study in rats with diltiazem at 0, 50, 100, 200 and 400 mg/kg/day from gestation day 15 to lactation/post-partum day 20, there was an increased incidence of stillbirths at 100 mg/kg/day, approximately 2 times (on a mg/m 2basis) the MRHD of CARDIZEM LA.

Risk Summary

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. Because of the potential for serious adverse reactions in nursing infants from diltiazem, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for diltiazem and any potential adverse effects on the breastfed child from diltiazem or from the underlying maternal condition.

Safety and effectiveness in pediatric patients have not been established.

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.

No dose adjustment is necessary.

No dose adjustment is likely to be needed for mild-moderate hepatic impairment.

The oral LD 50is 415 to 740 mg/kg in mice and 560 to 810 mg/kg in rats. The intravenous LD 50is 60 mg/kg in mice and 38 mg/kg in rats. The oral LD 50in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg.

{ "type": "p", "children": [], "text": "The oral LD\n \n 50is 415 to 740 mg/kg in mice and 560 to 810 mg/kg in rats. The intravenous LD\n \n 50is 60 mg/kg in mice and 38 mg/kg in rats. The oral LD\n \n 50in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg.\n\n " }

The toxic dose in man is not known. Blood levels after a standard dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases.

{ "type": "p", "children": [], "text": "The toxic dose in man is not known. Blood levels after a standard dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases." }

There have been 29 reports of diltiazem overdose in doses ranging from less than 1 g to 18 g. Sixteen of these reports involved multiple drug ingestions.

{ "type": "p", "children": [], "text": "There have been 29 reports of diltiazem overdose in doses ranging from less than 1 g to 18 g. Sixteen of these reports involved multiple drug ingestions." }

Twenty-two reports indicated patients had recovered from diltiazem overdose ranging from less than 1 g to 10.8 g. There were seven reports with a fatal outcome; although the amount of diltiazem ingested was unknown, multiple drug ingestions were confirmed in six of the seven reports.

{ "type": "p", "children": [], "text": "Twenty-two reports indicated patients had recovered from diltiazem overdose ranging from less than 1 g to 10.8 g. There were seven reports with a fatal outcome; although the amount of diltiazem ingested was unknown, multiple drug ingestions were confirmed in six of the seven reports." }

Events observed following diltiazem overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium.

{ "type": "p", "children": [], "text": "Events observed following diltiazem overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium." }

In the event of overdose or exaggerated response, institute appropriate supportive measures and gastrointestinal decontamination. 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. Based on the known pharmacological effects of diltiazem and/or reported clinical experiences, the following measures may be considered:

{ "type": "p", "children": [], "text": "In the event of overdose or exaggerated response, institute appropriate supportive measures and gastrointestinal decontamination. 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. Based on the known pharmacological effects of diltiazem and/or reported clinical experiences, the following measures may be considered:" }

Bradycardia:Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockage, administer isoproterenol cautiously.

{ "type": "p", "children": [], "text": "\nBradycardia:Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockage, administer isoproterenol cautiously.\n\n " }

High-degree AV Block:Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.

{ "type": "p", "children": [], "text": "\nHigh-degree AV Block:Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.\n\n " }

Cardiac Failure:Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.

{ "type": "p", "children": [], "text": "\nCardiac Failure:Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.\n\n " }

Hypotension:Use vasopressors (e.g., dopamine or norepinephrine).

{ "type": "p", "children": [], "text": "\nHypotension:Use vasopressors (e.g., dopamine or norepinephrine).\n\n " }

Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.

{ "type": "p", "children": [], "text": "Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician." }

CARDIZEM ®LA (diltiazem hydrochloride) is a nondihydropyridine calcium channel blocker (slow channel blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-benzothiazepin-4(5 H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2, 3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride, (+)- cis-. The structural formula is:

{ "type": "p", "children": [], "text": "CARDIZEM\n \n ®LA (diltiazem hydrochloride) is a nondihydropyridine calcium channel blocker (slow channel blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-benzothiazepin-4(5\n \n H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2, 3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride, (+)-\n \n cis-. The structural formula is:\n\n " }

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 450.99. CARDIZEM LA is formulated as a once-a-day extended-release tablet for oral administration containing 120 mg, 180 mg, 240 mg, 300 mg, 360 mg or 420 mg of diltiazem hydrochloride.

{ "type": "p", "children": [], "text": "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 450.99. CARDIZEM LA is formulated as a once-a-day extended-release tablet for oral administration containing 120 mg, 180 mg, 240 mg, 300 mg, 360 mg or 420 mg of diltiazem hydrochloride." }

Tablets also contain: carnauba wax, colloidal silicon dioxide, croscarmellose sodium, ethyl acrylate and methyl methacrylate copolymer dispersion, hydrogenated vegetable oil, hypromellose, magnesium stearate, microcrystalline cellulose, microcrystalline wax, polydextrose, polyethylene glycol, polysorbate, povidone, pregelatinized starch, simethicone, sodium starch glycolate, sucrose stearate, talc, and titanium dioxide.

{ "type": "p", "children": [], "text": "Tablets also contain: carnauba wax, colloidal silicon dioxide, croscarmellose sodium, ethyl acrylate and methyl methacrylate copolymer dispersion, hydrogenated vegetable oil, hypromellose, magnesium stearate, microcrystalline cellulose, microcrystalline wax, polydextrose, polyethylene glycol, polysorbate, povidone, pregelatinized starch, simethicone, sodium starch glycolate, sucrose stearate, talc, and titanium dioxide." }

The therapeutic effects of diltiazem are believed to be related to its ability to inhibit the cellular influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.

Hypertension:Diltiazem produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension; thus hypertensive individuals experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in normotensives.

Angina:Diltiazem has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal workloads. Diltiazem has been shown to be a potent dilator of coronary arteries, both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasms are inhibited by diltiazem.

In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. Diltiazem causes excitation-contraction uncoupling in various myocardial. Diltiazem produces relaxation of coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.

Like other calcium channel antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.

In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in normotensive individuals and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given workload. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end diastolic pressure have not been affected. Such data have no predictive value with respect to effects in patients with poor ventricular function, and increased heart failure has been reported in patients with preexisting impairment of ventricular function. There are as yet few data on the interaction of diltiazem and beta-blockers in patients with poor ventricular function. Resting heart rate is usually slightly reduced by diltiazem. Diltiazem decreases vascular resistance, increases cardiac output (by increasing stroke volume), and produces a slight decrease or no change in heart rate.

During dynamic exercise, increases in diastolic pressure are inhibited, while maximum achievable systolic pressure is usually reduced. Chronic therapy with diltiazem produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem reduces the renal and peripheral effects of angiotensin II. Hypertensive animal models respond to diltiazem with reductions in blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio.

Intravenous diltiazem hydrochloride 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. In a study involving single oral doses of diltiazem hydrochloride 300 mg in six normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first-degree AV block.

Diltiazem associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

Chronic oral administration of diltiazem hydrochloride to patients in doses of up to 540 mg/day has resulted in small increases in PR interval, and on occasion produces abnormal prolongation [see Warnings and Precautions (5.1)].

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous administration) of about 40%. Diltiazem undergoes extensive metabolism in which only 2% to 4% of the unchanged drug appears in the urine. Drugs that induce or inhibit hepatic microsomal enzymes may alter diltiazem disposition.

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.

In vitrobinding studies show diltiazem is 70% to 80% bound to plasma proteins. Competitive in vitroligand binding studies have also shown diltiazem hydrochloride binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0 to 4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of 10% to 20% of the parent drug and is 25% to 50% as potent as a coronary vasodilator as diltiazem. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50 to 200 ng/mL. There is a departure from linearity when dose strengths are increased; the half-life is slightly increased with dose. A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in bioavailability in the hepatically impaired patients. A single study in nine patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function.

CARDIZEM LA Tablets:A single 360 mg dose of CARDIZEM LA results in detectable plasma levels within 3 to 4 hours and peak plasma levels between 11 and 18 hours; absorption occurs throughout the dosing interval. The apparent elimination half-life for CARDIZEM LA Tablets after single or multiple dosing is 6 to 9 hours. When CARDIZEM LA Tablets were coadministered with a high fat content breakfast, diltiazem peak and systemic exposures were not affected indicating that the tablet can be administered without regard to food. As the dose of CARDIZEM LA Tablets is increased from 120 to 240 mg, area-under-the-curve (AUC) increases 2.5-fold.

Drug Interactions

Impact of Diltiazem on Other Coadministered Drugs

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- to 4-fold and the C maxby 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam also increased (1.5- to 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:Controlled and uncontrolled domestic studies suggest that concomitant use of diltiazem and beta-blockers is usually well tolerated, but available data are not sufficient to predict the effects of concomitant treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities.

Administration of diltiazem concomitantly 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. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted [see Warnings and Precautions (5.1, 5.2)].

Buspirone:In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and C max4.1-fold compared to placebo. The elimination half-life and T maxof 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 coadministration, and should be based on clinical assessment.

Carbamazepine:Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40% to 72% increase), resulting in toxicity in some cases.

Clonidine:Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with diltiazem. Monitor heart rate in patients receiving concomitant diltiazem and clonidine.

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 diltiazem therapy is initiated, adjusted, or discontinued. The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.

Digitalis:Administration of diltiazem with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Monitor digoxin levels when initiating, adjusting, and discontinuing diltiazem therapy to avoid possible over- or under-digitalization [see Warnings and Precautions (5.1)].

Quinidine:Diltiazem increases the AUC (0→∞)of quinidine by 51%, elimination half-life by 36%, and decreases its oral clearance by 33%. Monitor for quinidine adverse effects and adjust the dose adjusted.

Statins:Diltiazem has been shown to increase significantly the AUC of some statins. The risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4 may be increased with concomitant use of diltiazem. When possible, use a non-CYP3A4-metabolized statin together with diltiazem; otherwise, dose adjustments for both diltiazem and the statin should be considered along with close monitoring for signs and symptoms of any statin-related adverse events.

In a healthy volunteer cross-over study (N=10), coadministration of a single 20 mg dose of simvastatin at the end of a 14-day regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of diltiazem showed a greater fold increase in simvastatin exposure. Computer-based simulations showed that at a daily dose of 480 mg of diltiazem, an 8- to 9-fold mean increase in simvastatin AUC can be expected. If coadministration of simvastatin with diltiazem is required, limit the daily doses of simvastatin to 10 mg and diltiazem to 240 mg.

In a 10-subject randomized, open label, 4-way cross-over study, coadministration of diltiazem (120 mg BID diltiazem SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3- to 4-fold increase in mean lovastatin AUC and C maxversus lovastatin alone. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and C maxduring diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

Impact of Other Coadministered Drugs on Diltiazem Include, but Not Limited to:

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.

Cimetidine and Ranitidine: A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and AUC (53%) after a 1-week course of cimetidine at 1200 mg per day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, non -significant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P450, 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.

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 vitroor in vivoin mammalian cell assays or in vitroin 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.

In a randomized, double-blind, parallel-group, dose-response study involving 478 patients with essential hypertension, evening doses of CARDIZEM LA 120, 240, 360, and 540 mg were compared to placebo and to 360 mg administered in the morning. The mean reductions in diastolic blood pressure by ABPM at roughly 24 hours after the morning (4 AM to 8 AM) or evening (6 PM to 10 PM) administration (i.e., the time corresponding to expected trough serum concentrations) are shown in the table below:

<div class="scrollingtable"><table cellpadding="0.75pt" width="100%"> <col width="18%"/> <col width="18%"/> <col width="19%"/> <col width="18%"/> <col width="27%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule" colspan="5" valign="middle"> <p class="First"> <span class="Bold">Mean Change in Trough Diastolic Pressure by ABPM</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="middle"> <p class="First"> <span class="Bold">Evening Dosing</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Morning Dosing</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">120 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">240 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">360 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">540 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">360 mg</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">-2.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">-4.4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">-4.4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">-8.1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">-6.4</p> </td> </tr> </tbody> </table></div>

A second randomized, double-blind, parallel-group, dose-response study (N=258) evaluated CARDIZEM LA following morning doses of placebo or 120, 180, 300, or 540 mg. Diastolic blood pressure measured by supine office cuff sphygmomanometer at trough (7 AM to 9 AM) decreased in an apparently linear manner over the dosage range studied. Group mean changes for placebo, 120 mg, 180 mg, 300 mg and 540 mg were -2.6, -1.9, -5.4, -6.1, and -8.6 mm Hg, respectively.

Whether the time of administration impacts the clinical benefits of antihypertensive treatment is not known.

Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects.

The effects of CARDIZEM LA on angina were evaluated in a randomized, double-blind, parallel-group, dose-response trial of 311 patients with chronic stable angina. Evening doses of 180, 360, and 420 mg were compared to placebo and to 360 mg administered in the morning. All doses of CARDIZEM LA administered at night increased exercise tolerance when compared with placebo after 21 hours. The mean effect, placebo-subtracted, was 20 to 28 seconds for all three doses, and no dose-response was demonstrated. CARDIZEM LA, 360 mg, given in the morning, also improved exercise tolerance when measured 25 hours later. As expected, the effect was smaller than the effects measured only 21 hours following nighttime administration. CARDIZEM LA had a larger effect to increase exercise tolerance at peak serum concentrations than at trough.

CARDIZEM ®LA is supplied as capsule shaped, white film-coated tablets, debossed with “B” on one side and the diltiazem content (mg) on the other.

{ "type": "p", "children": [], "text": "CARDIZEM\n \n ®LA is supplied as capsule shaped, white film-coated tablets, debossed with “B” on one side and the diltiazem content (mg) on the other.\n\n " }

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <col width="17%"/> <col width="42%"/> <col width="42%"/> <thead> <tr class="First Last"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Strength</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">NDC #</span> <br/> <span class="Bold">Bottles of 30</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">NDC #</span> <br/> <span class="Bold">Bottles of 90</span></th> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">120 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0187-2045-30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0187-2045-90</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">180 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0187-2046-30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0187-2046-90</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">240 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0187-2047-30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0187-2047-90</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">300 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0187-2048-30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0187-2048-90</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">360 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0187-2049-30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0187-2049-90</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">420 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0187-2050-30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0187-2050-90</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0pt\" width=\"100%\">\n<col width=\"17%\"/>\n<col width=\"42%\"/>\n<col width=\"42%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\"><span class=\"Bold\">Strength</span></th><th align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\"><span class=\"Bold\">NDC #</span>\n<br/>\n<span class=\"Bold\">Bottles of 30</span></th><th align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\"><span class=\"Bold\">NDC #</span>\n<br/>\n<span class=\"Bold\">Bottles of 90</span></th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">120 mg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">0187-2045-30</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">0187-2045-90</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">180 mg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0187-2046-30</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0187-2046-90</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">240 mg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0187-2047-30</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0187-2047-90</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">300 mg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0187-2048-30</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0187-2048-90</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">360 mg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0187-2049-30</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0187-2049-90</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">420 mg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0187-2050-30</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0187-2050-90</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Storage conditions: Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Storage conditions: Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]." }

Avoid excessive humidity and temperatures above 30°C (86°F).

{ "type": "p", "children": [], "text": "Avoid excessive humidity and temperatures above 30°C (86°F)." }

Dispense in tight, light resistant container as defined in USP.

{ "type": "p", "children": [], "text": "Dispense in tight, light resistant container as defined in USP." }

Advise patients:

{ "type": "p", "children": [], "text": "Advise patients:" }

{ "type": "ul", "children": [ "That the CARDIZEM LA tablet should be swallowed whole and not chewed or crushed.", "To consult the physician who prescribed CARDIZEM LA before taking or stopping any other medications, including over-the-counter products or nutritional supplements, such as St. John’s wort.", "To contact the physician who prescribed CARDIZEM LA or any other physician immediately if they experience possible adverse reactions, including bradycardia, arrhythmias, symptoms indicative of hypotension or heart failure, hepatic and skin reactions.", "To consult their physician if they become pregnant while taking CARDIZEM LA or plan to become pregnant." ], "text": "" }

Manufactured for: Bausch Health US, LLC Bridgewater, NJ 08807 USA

{ "type": "p", "children": [], "text": "\nManufactured for: \n Bausch Health US, LLC \n Bridgewater, NJ 08807 USA\n\n " }

Manufactured by: Bausch Health Companies Inc. Steinbach, MB R5G 1Z7, Canada

{ "type": "p", "children": [], "text": "\nManufactured by: \n Bausch Health Companies Inc. \n Steinbach, MB R5G 1Z7, Canada\n\n " }

Cardizem is a trademark of Bausch Health Companies Inc. or its affiliates.

{ "type": "p", "children": [], "text": "Cardizem is a trademark of Bausch Health Companies Inc. or its affiliates." }

© 2025 Bausch Health Companies Inc. or its affiliates

{ "type": "p", "children": [], "text": "© 2025 Bausch Health Companies Inc. or its affiliates" }

9457003

{ "type": "p", "children": [], "text": "9457003" }

NDC0187-2045-90

{ "type": "p", "children": [], "text": "\nNDC0187-2045-90\n\n " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

CARDIZEM ®LA (Diltiazem Hydrochloride) Extended-Release Tablets

{ "type": "p", "children": [], "text": "\nCARDIZEM\n \n ®LA\n \n \n (Diltiazem Hydrochloride) \n Extended-Release Tablets\n\n " }

120 mg

{ "type": "p", "children": [], "text": "\n120 mg\n" }

90 Tablets

{ "type": "p", "children": [], "text": "\n90 Tablets\n" }

BAUSCHHealth

{ "type": "p", "children": [], "text": "\nBAUSCHHealth\n\n " }

NDC0187-2046-90

{ "type": "p", "children": [], "text": "\nNDC0187-2046-90\n\n " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

CARDIZEM ®LA (Diltiazem Hydrochloride) Extended-Release Tablets

{ "type": "p", "children": [], "text": "\nCARDIZEM\n \n ®LA\n \n \n (Diltiazem Hydrochloride) \n Extended-Release Tablets\n\n " }

180 mg

{ "type": "p", "children": [], "text": "\n180 mg\n" }

90 Tablets

{ "type": "p", "children": [], "text": "\n90 Tablets\n" }

BAUSCHHealth

{ "type": "p", "children": [], "text": "\nBAUSCHHealth\n\n " }

NDC0187-2047-90

{ "type": "p", "children": [], "text": "\nNDC0187-2047-90\n\n " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

CARDIZEM ®LA (Diltiazem Hydrochloride) Extended-Release Tablets

{ "type": "p", "children": [], "text": "\nCARDIZEM\n \n ®LA\n \n \n (Diltiazem Hydrochloride) \n Extended-Release Tablets\n\n " }

240 mg

{ "type": "p", "children": [], "text": "\n240 mg\n" }

90 Tablets

{ "type": "p", "children": [], "text": "\n90 Tablets\n" }

BAUSCHHealth

{ "type": "p", "children": [], "text": "\nBAUSCHHealth\n\n " }

NDC0187-2048-90

{ "type": "p", "children": [], "text": "\nNDC0187-2048-90\n\n " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

CARDIZEM ®LA (Diltiazem Hydrochloride) Extended-Release Tablets

{ "type": "p", "children": [], "text": "\nCARDIZEM\n \n ®LA\n \n \n (Diltiazem Hydrochloride) \n Extended-Release Tablets\n\n " }

300 mg

{ "type": "p", "children": [], "text": "\n300 mg\n" }

90 Tablets

{ "type": "p", "children": [], "text": "\n90 Tablets\n" }

BAUSCHHealth

{ "type": "p", "children": [], "text": "\nBAUSCHHealth\n\n " }

NDC0187-2049-90

{ "type": "p", "children": [], "text": "\nNDC0187-2049-90\n\n " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

CARDIZEM ®LA (Diltiazem Hydrochloride) Extended-Release Tablets

{ "type": "p", "children": [], "text": "\nCARDIZEM\n \n ®LA\n \n \n (Diltiazem Hydrochloride) \n Extended-Release Tablets\n\n " }

360 mg

{ "type": "p", "children": [], "text": "\n360 mg\n" }

90 Tablets

{ "type": "p", "children": [], "text": "\n90 Tablets\n" }

BAUSCH Health

{ "type": "p", "children": [], "text": "\nBAUSCH Health\n" }

NDC0187-2050-90

{ "type": "p", "children": [], "text": "\nNDC0187-2050-90\n\n " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

CARDIZEM ®LA (Diltiazem Hydrochloride) Extended-Release Tablets

{ "type": "p", "children": [], "text": "\nCARDIZEM\n \n ®LA\n \n \n (Diltiazem Hydrochloride) \n Extended-Release Tablets\n\n " }

420 mg

{ "type": "p", "children": [], "text": "\n420 mg\n" }

90 Tablets

{ "type": "p", "children": [], "text": "\n90 Tablets\n" }

BAUSCHHealth

{ "type": "p", "children": [], "text": "\nBAUSCHHealth\n\n " }