FDA label 04e52eac-ba13-487a-eddd-8614176bbb03

WARNINGS Cardiac Conduction. Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (13 of 3290 patients or 0.40%). 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 ). Congestive Heart Failure. Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). An acute study of oral diltiazem in patients with impaired ventricular function (ejection fraction 24% ± 6%) showed improvement in indices of ventricular function without significant decrease in contractile function (dp/dt). Worsening of congestive heart failure has been reported in patients with preexisting impairment of ventricular function. Experience with the use of diltiazem in combination with beta-blockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination. Hypotension. Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension. Acute Hepatic Injury. Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed in clinical studies. Such elevations were usually transient and frequently resolved even with continued diltiazem treatment. In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions tended to occur early after therapy initiation (1 to 8 weeks) and have been reversible upon discontinuation of drug therapy. The relationship to diltiazem is uncertain in some cases, but probable in some (see PRECAUTIONS ).

ADVERSE REACTIONS Serious adverse reactions have been rare in studies carried out to date, but it should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies.. In the hypertension study, 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. Placebo Diltiazem hydrochloride extended-release Adverse Reactions (MedDRA Term) n= 120 # pts (%) 120-360 mg n= 501 # pts (%) 540 mg n= 123 # pts (%) Edema lower limb 4 (3) 24 (5) 10 (8) Sinus congestion 0 (0) 2 (1) 2 (2) Rash NOS 0 (0) 3 (1) 2 (2) 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 clinical trials of other diltiazem formulations involving over 3200 patients, the most common events (i.e., greater than 1%) were edema (4.6%), headache (4.6%), dizziness (3.5%), asthenia (2.6%), first-degree AV block (2.4%), bradycardia (1.7%), flushing (1.4%), nausea (1.4%), and rash (1.2%). In addition, the following events have been reported infrequently (less than 1%) in angina or hypertension trials: Cardiovascular: Angina, arrhythmia, AV block (second- or third-degree), bundle branch block, congestive heart failure, ECG abnormalities, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles. 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, mild elevations of SGOT, SGPT, LDH, and alkaline phosphatase (see WARNINGS, Acute Hepatic Injury ), thirst, vomiting, weight increase. Dermatological: Petechiae, photosensitivity, pruritus, urticaria. Other: Amblyopia, CPK increase, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties. The following postmarketing events have been reported infrequently in patients receiving Cardizem: acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema (including facial or periorbital edema), asystole, erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), exfoliative dermatitis, 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. However, a definitive cause and effect relationship between these events and Cardizem: therapy is yet to be established.

<table width="75%"> <col width="25%"/> <col width="17%"/> <col width="17%"/> <col width="16%"/> <thead> <tr> <th styleCode="Lrule Toprule " align="left" valign="top"> </th> <th styleCode="Botrule Lrule Toprule " align="left" valign="bottom"> <content styleCode="bold">Placebo</content> </th> <th styleCode="Rrule Botrule Lrule Toprule " colspan="2" align="center" valign="top"> <content styleCode="bold">Diltiazem hydrochloride extended-release</content> </th> </tr> <tr> <th styleCode="Lrule Botrule " align="left" valign="bottom"> <content styleCode="bold">Adverse Reactions (MedDRA Term)</content> </th> <th styleCode="Lrule Botrule " align="left" valign="bottom"> <content styleCode="bold">n= 120</content> <content styleCode="bold"># pts (%) </content> </th> <th styleCode="Lrule Botrule " align="left" valign="bottom"> <content styleCode="bold">120-360 mg</content> <content styleCode="bold">n= 501</content> <content styleCode="bold"># pts (%)</content> </th> <th styleCode="Rrule Lrule Botrule " align="left" valign="bottom"> <content styleCode="bold">540 mg</content> <content styleCode="bold">n= 123</content> <content styleCode="bold"># pts (%)</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Toprule "> <paragraph>Edema lower limb</paragraph> </td> <td styleCode="Lrule Toprule "> <paragraph>4 (3)</paragraph> </td> <td styleCode="Lrule Toprule "> <paragraph>24 (5)</paragraph> </td> <td styleCode="Rrule Lrule Toprule "> <paragraph>10 (8)</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Sinus congestion</paragraph> </td> <td styleCode="Lrule "> <paragraph>0 (0)</paragraph> </td> <td styleCode="Lrule "> <paragraph>2 (1)</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>2 (2)</paragraph> </td> </tr> <tr> <td styleCode="Botrule Lrule "> <paragraph>Rash NOS</paragraph> </td> <td styleCode="Botrule Lrule "> <paragraph>0 (0)</paragraph> </td> <td styleCode="Botrule Lrule "> <paragraph>3 (1)</paragraph> </td> <td styleCode="Rrule Botrule Lrule "> <paragraph>2 (2)</paragraph> </td> </tr> </tbody> </table>