ADVERSE REACTIONS
Serious adverse reactions to diltiazem hydrochloride have been rare in studies with other formulations, as well as with Dilacor XR®. It should be recognized, however, that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies.
Hypertension: The most common adverse events (frequency ≥1%) in placebo-controlled, clinical hypertension studies with Dilacor XR using daily doses up to 540 mg, are listed in the table below with placebo-treated patients included for comparison.
MOST COMMON ADVERSE EVENTS IN DOUBLE-BLIND, PLACEBO-CONTROLLED HYPERTENSION TRIALS | Dilacor XR®* | Placebo |
| Adverse Events | n=303 | n=87 |
| (COSTART Term) | # pts (%) | # pts (%) |
| *Adverse events occurring in 1% or more of patients receiving Dilacor XR. |
| rhinitis | 29 (9.6) | 7 (8.0) |
| headache | 27 (8.9) | 12 (13.8) |
| pharyngitis | 17 (5.6) | 4 (4.6) |
| constipation | 11 (3.6) | 2 (2.3) |
| cough increase | 9 (3.0) | 2 (2.3) |
| flu syndrome | 7 (2.3) | 1 (1.1) |
| edema, peripheral | 7 (2.3) | 0 (0.0) |
| myalgia | 7 (2.3) | 0 (0.0) |
| diarrhea | 6 (2.0) | 0 (0.0) |
| vomiting | 6 (2.0) | 0 (0.0) |
| sinusitis | 6 (2.0) | 1 (1.1) |
| asthenia | 5 (1.7) | 0 (0.0) |
| pain, back | 5 (1.7) | 2 (2.3) |
| nausea | 5 (1.7) | 1 (1.1) |
| dyspepsia | 4 (1.3) | 0 (0.0) |
| vasodilatation | 4 (1.3) | 0 (0.0) |
| injury, accident | 4 (1.3) | 0 (0.0) |
| pain, abdominal | 3 (1.0) | 0 (0.0) |
| arthrosis | 3 (1.0) | 0 (0.0) |
| insomnia | 3 (1.0) | 0 (0.0) |
| dyspnea | 3 (1.0) | 0 (0.0) |
| rash | 3 (1.0) | 1 (1.1) |
| tinnitus | 3 (1.0) | 0 (0.0) |
Angina: The most common adverse events (frequency ≥1%) in a placebo-controlled, short-term (2 week) clinical angina study with Dilacor XR are listed in the table below with placebo-treated patients included for comparison. In this trial, following a placebo phase, patients were randomly assigned to once daily doses of either 120, 240, or 480 mg of Dilacor XR.
MOST COMMON ADVERSE EVENTS IN A DOUBLE-BLIND, PLACEBO-CONTROLLED SHORT-TERM, ANGINA TRIALS | Dilacor XR®* | Placebo |
| Adverse Events | n=139 | n=50 |
| (COSTART Term) | # pts (%) | # pts (%) |
| *Adverse events occurring in 1% or more of patients receiving Dilacor XR. |
| asthenia | 5 (3.6) | 2 (4.0) |
| headache | 4 (2.9) | 3 (6.0) |
| pain, back | 4 (2.9) | 1 (2.0) |
| rhinitis | 4 (2.9) | 1 (2.0) |
| constipation | 3 (2.2) | 1 (2.0) |
| nausea | 3 (2.2) | 0 (0.0) |
| edema, peripheral | 3 (2.2) | 1 (2.0) |
| dizziness | 3 (2.2) | 0 (0.0) |
| cough, increased | 3 (2.2) | 0 (0.0) |
| bradycardia | 2 (1.4) | 0 (0.0) |
| fibrillation, atrial | 2 (1.4) | 0 (0.0) |
| arthralgia | 2 (1.4) | 0 (0.0) |
| dream, abnormal | 2 (1.4) | 0 (0.0) |
| dyspnea | 2 (1.4) | 0 (0.0) |
| pharyngitis | 2 (1.4) | 1 (2.0) |
Infrequent Adverse Events: The following additional events (COSTART Terms), listed by body system, were reported infrequently (less than 1%) in all subjects, hypertensive (n=425) or angina (n-318) patients who received Dilacor XR, or with other formulations of diltiazem.
Hypertension: Cardiovascular: First-degree AV block, arrhythmia, postural hypotension, tachycardia, pallor, palpitations, phlebitis, ECG abnormality, ST elevation.
Nervous System: Vertigo, hypertonia, paresthesia, dizziness, somnolence.
Digestive System: Dry mouth, anorexia, tooth disorder, eructation.
Skin and Appendages: Sweating, urticaria, skin hypertrophy (nevus).
Respiratory System: Epistaxis, bronchitis, respiratory disorder.
Urogenital System: Cystitis, kidney calculus, impotence, dysmenorrhea, vaginitis, prostate disease.
Metabolic and Nutritional Disorders: Gout, edema.
Musculoskeletal System: Arthralgia, bursitis, bone pain.
Hemic and Lymphatic System: Lymphadenopathy.
Body as a Whole: Pain, unevaluable reaction, neck pain, neck rigidity, fever, chest pain, malaise.
Special Senses: Amblyopia (blurred vision), ear pain.
Angina: Cardiovascular: Palpitations, AV block, sinus bradycardia, bigeminal extrasystole, angina pectoris, hypertension, hypotension, myocardial infarct, myocardial ischemia, syncope, vasodilatation, ventricular extrasystole.
Nervous System: Abnormal thinking, neuropathy, paresthesia.
Digestive System: Diarrhea, dyspepsia, vomiting, colitis, flatulence, GI hemorrhage, stomach ulcers.
Skin and Appendages: Contact dermatitis, pruritus, sweating.
Respiratory System: Respiratory distress.
Urogenital System: Kidney failure, pyelonephritis, urinary tract infection.
Metabolic and Nutritional Disorders: Weight increase.
Musculoskeletal System: Myalgia.
Body as a Whole: Chest pain, accidental injury, infection.
Special Senses: Eye hemorrhage, ophthalmitis, otitis media, taste perversion, tinnitus.
There have been post-marketing reports of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of diltiazem hydrochloride.
OVERDOSAGE OR EXAGGERATED RESPONSE
Several literature reports have identified cases of diltiazem hydrochloride overdose, some with multiple drug ingestion, with both fatal and non-fatal outcomes. The reported events affected multiple body systems including the cardiovascular system (bradycardia, complete heart block, asystole, cardiac failure, arrhythmia, atrial fibrillation, palpitations, hypotension, ischemia, ECG changes), respiratory system (respiratory failure, hypoxia, dyspnea, pulmonary edema), central nervous system (loss of consciousness, convulsions, dizziness, confusion, agitation), gastrointestinal system (nausea, vomiting), skin and appendages (increased sweating), and other systems (hypotonia, iliac artery thrombosis, metabolic acidosis, increased blood glucose). The administration of ipecac to induce vomiting and activated charcoal to reduce drug absorption have been advocated as initial means of intervention. In addition to gastric lavage, the following measures should also be considered:
Bradycardia: administer atropine (0.6 mg to 1 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.
High-Degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.
Cardiac Failure: Administer inotropic agents (dopamine or dobutamine) and diuretics.
Hypotension: Vasopressors (e.g., dopamine or levarterenol bitartrate).
Actual treatment and dosage should depend on the severity of the clinical situation as well as the judgment and experience of the treating physician.
Due to extensive metabolism, plasma concentrations after a standard dose of diltiazem can vary over tenfold, which significantly limits their value in evaluating cases of overdosage.
Charcoal hemoperfusion has been used successfully as an adjunct therapy to hasten drug elimination. Overdoses with as much as 10.8 grams of oral diltiazem have been successfully treated using appropriate supportive care.
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