<p><strong>Clinical Toxicity and Overdose</strong></p><p>The oral LD<sub>50</sub> ranges from 415 to 740mg/kg in mice and 560 to 810 mg/kg in rats. The oral LD<sub>50</sub> in dogs is considered to be in excess of 50 mg/kg. A dose of 360 mg/kg resulted in lethality in monkeys. The intravenous LD<sub>50</sub> is 60 mg/kg in mice and 38 mg/kg in rats. </p><p>Cases of overdose from doses ranging from less than 1 g to 18 g have been reported with diltiazem, with several cases involving multiple drug ingestions resulting in death. Overdoses were associated with bradycardia, hypotension, heart block, and cardiac failure that may manifest as dizziness, lightheadedness, and fatigue.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Diltiazem - StatPearls - NCBI Bookshelf" href="#reference-L6289">9</a></sup> Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. Diltiazem overdose should be responded with appropriate supportive measures and gastrointestinal decontamination. Bradycardia and heart block can be treated with atropine at doses ranging from 0.60 to 1.0 mg. In the case of bradycardia, if there is no response to vagal blockage, cautious administration of isoproterenol should be considered. Cardiac pacing can also be used to treat fixed high-degree AV block. In the case of heart failure, blood pressure may be maintained with the use of fluids and vasopressors, as well as inotropic agents such as <a href="https://go.drugbank.com/drugs/DB01064">isoproterenol</a>, <a href="https://go.drugbank.com/drugs/DB00988">dopamine</a>, or <a href="https://go.drugbank.com/drugs/DB00841">dobutamine</a>. Other appropriate measures include ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium. Diltiazem does not appear to be removed by peritoneal or hemodialysis.<sup class="text-reference-group"><a class="reference-popover-link" data-content="CARDIZEM® LA (diltiazem hydrochloride) extended-release tablets - FDA Label" href="#reference-L10556">12</a></sup></p><p><strong>Non-clinical toxicity</strong></p><p>In a 24-month study in rats receiving oral doses of up to 100 mg/kg/day, there was no evidence of carcinogenicity. There was also no mutagenic response <em>in vitro</em> or <em>in vivo</em> in mammalian cell assays or <em>in vitro</em> bacterial assays. No evidence of impaired fertility was observed in a study performed in male and female rats receiving oral doses of up to 100 mg/kg/day.<sup class="text-reference-group"><a class="reference-popover-link" data-content="CARDIZEM® LA (diltiazem hydrochloride) extended-release tablets - FDA Label" href="#reference-L10556">12</a></sup></p><p><strong>Pregnancy and Lactation</strong></p><p>In reproduction studies in animals, administration of diltiazem at doses ranging from five to twenty times the daily recommended human therapeutic dose resulted in cases of the embryo and fetal lethality and skeletal abnormalities, and an increase in the risk of stillbirths. There have been no up-to-date controlled studies that investigated the use of diltiazem in pregnant women. The use of diltiazem in pregnant women should be undertaken only if the potential benefit justifies the risk to the fetus.<sup class="text-reference-group"><a class="reference-popover-link" data-content="CARDIZEM® LA (diltiazem hydrochloride) extended-release tablets - FDA Label" href="#reference-L10556">12</a></sup> Diltiazem is excreted in human milk, where one report suggests that the concentrations in breast milk may approximate serum levels; therefore, the decision should be made to either discontinue nursing or the use of the drug after careful consideration of the clinical necessity of diltiazem therapy in the nursing mother.<sup class="text-reference-group"><a class="reference-popover-link" data-content="CARDIZEM® LA (diltiazem hydrochloride) extended-release tablets - FDA Label" href="#reference-L10556">12</a></sup></p><p><strong>Use in special populations</strong></p><p>As there is limited information on the variable effects of diltiazem in geriatric patients, the initial therapy of diltiazem should involve 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. Currently, there are no specific dosing guidelines for patients with renal or hepatic impairment.<sup class="text-reference-group"><a class="reference-popover-link" data-content="CARDIZEM® LA (diltiazem hydrochloride) extended-release tablets - FDA Label" href="#reference-L10556">12</a></sup></p>