Yes

Calcium Channel Blocker

Capsule: Essential hypertension (alone or in combination) - sustained release only; chronic stable angina or angina from coronary artery spasm

Injection: Atrial fibrillation or atrial flutter; paroxysmal supraventricular tachycardia (PSVT)

C

Clinical effects on the fetus: Teratogenic and embryotoxic effects have been demonstrated in small animals given doses 5-10 times the adult dose (mg/kg)

Breast-feeding/lactation: Freely diffuses into breast milk; however, the American Academy of Pediatrics considers diltiazem to be compatible with breast-feeding. Available evidence suggests safe use during breast-feeding.

Hypersensitivity to diltiazem or any component; sick sinus syndrome; second- or third- degree AV block (except in patients with a functioning artificial pacemaker); hypotension (systolic <90 mm Hg); acute MI and pulmonary congestion by x-ray

Concomitant use with beta-blockers or digoxin can result in conduction disturbances. Avoid concurrent I.V. use of diltiazem and a beta-blocker - monitor closely when I.V. diltiazem is used. Use caution in left ventricular dysfunction and CHF (can exacerbate condition). Symptomatic hypotension can occur. Use with caution in hepatic or renal dysfunction.

>10%: Gastrointestinal: Gingival hyperplasia (21%)

1% to 10%:

Cardiovascular: Sinus bradycardia (1.5% to 6%), first-degree A-V block (1.8% to 7.6%), EKG abnormality (4.1%), peripheral edema (dose-related 5.4% to 8%), flushing (1.9% to 3%), hypotension (1%), palpitations (1.3%)

Central nervous system: Dizziness (3.4% to 7%), headache (4.5% to 12%), somnolence (1.3%), insomnia (1%)

Gastrointestinal: Nausea (1.3% to 1.6%), constipation (1.6%), dyspepsia (1.3%)

Neuromuscular & skeletal: Weakness (2.8% to 5%)

Dermatological: Rash (1& to 1.5%)

Renal: Polyuria (1.3%)

<1% (Limited to important or life-threatening symptoms): Angina, arrhythmia, second- or third-degree AV block, bundle branch block, congestive heart failure, syncope, tachycardia, ventricular extrasystoles, abnormal dreams, amnesia, depression, gait abnormalities, hallucinations, nervousness, paresthesia, personality change, tremor, anorexia, diarrhea, dry mouth, dysgeusia, thirst, vomiting, weight gain, petechiae, photosensitivity, pruritus, urticaria, amblyopia, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, sexual difficulties, myoclonus, tinnitus

Case reports: Agranulocytosis, leukocytopenia (overdose), thrombocytopenia, akathisia, mania, psychosis, Parkinsonian-like syndrome, TEN, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, gynecomastia

The primary cardiac symptoms of calcium blocker overdose includes hypotension and bradycardia. The hypotension is caused by peripheral vasodilation, myocardial depression, and bradycardia. Bradycardia results from sinus bradycardia, second- or third-degree atrioventricular block, or sinus arrest with junctional rhythm. Intraventricular conduction is usually not affected so QRS duration is normal (verapamil does prolong the P-R interval and bepridil prolongs the Q-T and may cause ventricular arrhythmias, including torsade de pointes).

In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this agent when larger doses (approaching 1 gram per hour for more than 24 hours) of calcium chloride was administered.

CYP3A3/4 enzyme substrate; CYP3A3/4, 1A2, 2D6 enzyme inhibitor

Amiodarone use may lead to bradycardia, other conduction delays, and decreased cardiac output; monitor closely if using together.

Azole antifungals may inhibit the calcium channel blocker's metabolism; avoid this combination. Try an antifungal like terbinafine (if appropriate) or monitor closely for altered effect of the calcium channel blocker.

Beta-blockers may have increased pharmacodynamic interactions with diltiazem (see Warnings/Precautions).

Calcium may reduce the calcium channel blocker's effects, particularly hypotension.

Carbamazepine's serum concentration is increased and toxicity may result; avoid this combination.

Cimetidine reduced diltiazem's metabolism; consider an alternative H₂ antagonist.

Cyclosporine's serum concentrations are increased by diltiazem; avoid the combination. Use another calcium channel blocker or monitor cyclosporine trough levels and renal function closely.

Digoxin's serum concentration can be increased in some patients; monitor for increased effects of digoxin.

HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, lovastatin, simvastatin): Serum concentration will likely be increased; consider pravastatin/fluvastatin or a dihydropyridine calcium channel blocker.

Lithium neurotoxicity may result when diltiazem is added; monitor lithium levels.

Midazolam's plasma concentration is increased by diltiazem; monitor for prolonged CNS depression.

Moricizine's serum concentration is increased; monitor clinical response closely.

Nafcillin decreases plasma concentration of diltiazem; avoid this combination.

Nitroprusside's dose required reduction in patients started on diltiazem; monitor blood pressure.

Protease inhibitor like amprenavir and ritonavir may increase diltiazem's serum concentration.

Rifampin increases the metabolism of calcium channel blockers; adjust the dose of the calcium channel blocker to maintain efficacy.

Tacrolimus's serum concentrations are increased by diltiazem; avoid the combination. Use another calcium channel blocker or monitor tacrolimus trough levels and renal function closely.

Store injections in refrigerator at 2°C to 8°C (36°F to 46°F); stable for 24 hours

Inhibits calcium ion from entering the "slow channels" or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina

Onset of action: Oral: 30-60 minutes (including sustained release)

Absorption: 80% to 90%

Time to peak serum concentration: Short-acting tablets: Within 2-3 hours; Sustained release: 6-11 hours

Distribution: V_d: 3-13 L/kg; appears in breast milk

Protein binding: 77% to 85%

Metabolism: Extensive first-pass metabolism; metabolized in the liver; following single I.V. injection, plasma concentrations of N-monodesmethyldiltiazem and desacetyldiltiazem are typically undetectable; however, these metabolites accumulate to detectable concentrations following 24-hour constant rate infusion. N-monodesmethyldiltiazem appears to have 20% of the potency of diltiazem; desacetyldiltiazem is about 50% as potent as the parent compound.

Bioavailability: ~40% to 60% due to significant first-pass effect

Half-life: 4-6 hours, may increase with renal impairment; 5-7 hours with sustained release

Elimination: In urine and bile mostly as metabolites

Adults:

Sustained-release capsules:

Cardizem® SR: Initial: 60-120 mg twice daily; adjust to maximum antihypertensive effect (usually within 14 days); usual range: 240-360 mg/day

Cardizem® CD, Tiazac™: Hypertension: Total daily dose of short-acting administered once daily or initially 180 or 240 mg once daily; adjust to maximum effect (usually within 14 days); maximum: 480 mg/day; usual range: 240-360 mg/day

Cardizem® CD: Angina: Initial: 120-180 mg once daily; maximum: 480 mg once/day

Dilacor™ XR:

Hypertension: 180-240 mg once daily; maximum: 540 mg/day; usual range: 180-480 mg/day; use lower dose in elderly

Angina: Initial: 120 mg/day; titrate slowly over 7-14 days up to 480 mg/day, as needed

I.V. (requires an infusion pump):

• Initial bolus dose: 0.25 mg/kg actual body weight over 2 minutes (average adult dose: 20 mg)
• Repeat bolus dose (may be administered after 15 minutes if the response is inadequate.): 0.35 mg/kg actual body weight over 2 minutes (average adult dose: 25 mg)
• Continuous infusion (infusions >24 hours or infusion rates >15 mg/hour are not recommended.): Initial infusion rate of 10 mg/hour; rate may be increased in 5 mg/hour increments up to 15 mg/hour as needed; some patients may respond to an initial rate of 5 mg/hour.

If Cardizem® injectable is administered by continuous infusion for >24 hours, the possibility of decreased diltiazem clearance, prolonged elimination half-life, and increased diltiazem and/or diltiazem metabolite plasma concentrations should be considered.

Conversion from I.V. diltiazem to oral diltiazem: Start oral approximately 3 hours after bolus dose.

Oral dose (mg/day) is approximately equal to [rate (mg/hour) x 3 + 3] x 10.

3 mg/hour = 120 mg/day

5 mg/hour = 180 mg/day

7 mg/hour = 240 mg/day

11 mg/hour = 360 mg/day

Dosing comments in renal/hepatic impairment: Use with caution as extensively metabolized by the liver and excreted in the kidneys and bile.

Dialysis: Not removed by hemo- or peritoneal dialysis; supplemental dose is not necessary.

Alcohol: Avoid use

Sustained release capsules may be opened and sprinkled on a spoonful of applesauce. Applesauce should be swallowed without chewing, followed by drinking a glass of water.

Liver function tests, blood pressure, EKG

Diltiazem is an effective antihypertensive alone or in combination with other agents. Antihypertensive therapy should be individualized with consideration given to the patient's concomitant diseases and compelling indications for therapy.

Diltiazem may be administered intravenously in the acute setting to attain ventricular rate control in patients with atrial fibrillation or flutter. Patients who respond, defined in general as at least a 20% decrease in ventricular response rate or attaining a rate <100 beats/minute, can be continued on oral therapy to maintain control. It is important to consider the potential drug interaction with digoxin, as these agents are both used in this setting.

May cause dizziness, insomnia, nervousness, or sedation

May produce leukopenia; use caution with clozapine and carbamazepine; lithium levels may be increased or decreased; monitor serum lithium levels; carbamazepine levels may be increased; monitor levels

No information available to require special precautions

Calcium channel blockers cause gingival hyperplasia in approximately 1% of patients. There have been fewer reports with diltiazem than with other CCBs. The hyperplasia will usually disappear with cessation of drug therapy. Consultation with physician is suggested.

Oral: Take as directed; do not alter dosage or discontinue therapy without consulting prescriber. Do not crush or chew extended release form. Avoid (or limit) alcohol and caffeine. You may experience dizziness or lightheadedness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea or vomiting (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, dietary fiber, fruit, or fluid may help); diarrhea (buttermilk, boiled milk, or yogurt may help). Report chest pain, palpitations, irregular heartbeat, unusual cough, difficulty breathing, swelling of extremities, muscle tremors or weakness, confusion or acute lethargy, or skin rash. Pregnancy precautions: Inform prescriber if you are or intend to be pregnant.

Do not crush sustained release capsules

Capsule, sustained release, as hydrochloride: 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg

Cardizem® CD: 120 mg, 180 mg, 240 mg, 300 mg, 360 mg

Cardizem® SR: 60 mg, 90 mg, 120 mg

Cartia® XT: 120 mg, 180 mg, 240 mg, 300 mg

Dilacor™ XR: 180 mg, 240 mg

Diltia XT®: 120 mg, 180 mg, 240 mg

Tiazac®: 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg

Injection, as hydrochloride: 5 mg/mL (5 mL, 10 mL)

Cardizem®: 5 mg/mL (5 mL, 10 mL)

Tablet, as hydrochloride (Cardizem®): 30 mg, 60 mg, 90 mg, 120 mg

Tablet, extended release, as hydrochloride (Tiamate®): 120 mg, 180 mg, 240 mg

Diltiazem 12 mg/mL was found to be stable for up to 60 days at 5°C and 25°C in a 1:1 mixture of Ora-Sweet® and Ora-Plus®, a 1:1 mixture of Ora-Sweet® SF and Ora-Plus® and of cherry syrup

Anthony T, Jastremski M, Elliott W, et al, "Charcoal Hemoperfusion for the Treatment of a Combined Diltiazem and Metoprolol Overdose," Ann Emerg Med, 1986, 15(11):1344-8.

Avila JR, Bejarano D, Gonzalez ML, et al, "Elevation of Hepatic Enzymes After Cutaneous Reaction Caused by Diltiazem," Ann Pharmacother, 1995, 29(3):317-8.

Bertorini TE, Palmieri GMA, Griffin JW, et al, "Effect of Chronic Treatment With the Calcium Antagonist Diltiazem in Duchenne Muscular Dystrophy," Neurology, 1988, 38(4):609-13.

Ellenbogen KA, Dias VC, and Cardello FP, "Safety and Efficacy of Intravenous Diltiazem in Atrial Fibrillation or Atrial Flutter," Am J Cardiol, 1995, 75(1):45-9.

Fauville JP, Hantson P, Honore P, et al, "Severe Diltiazem Poisoning With Intestinal Pseudo-Obstruction: Case Report and Toxicological Data," J Toxicol Clin Toxicol, 1995, 33(3):273-7.

Ferner RE, Odemuyiwa O, Field AB, et al, "Pharmacokinetics and Toxic Effects of Diltiazem in Massive Overdose," Hum Toxicol, 1989, 8(6):497-9.

Howarth DM, Dawson AH, Smith AJ, et al, "Calcium Channel Blocking Drug Overdose: An Australian Series," Hum Exp Toxicol, 1994, 13(3):161-6.

Kalin JR, Wood KM, and Lee AJ, "A Possible Suicide by Diltiazem Overdose," J Anal Toxicol, 1994, 18(3):180-2.

Proano L, Chiang WK, and Wang RY, "Calcium Channel Blocker Overdose," Am J Emerg Med, 1995, 13(4):444-50.

Roberts D, Honcharik N, Sitar DS, et al, "Diltiazem Overdose: Pharmacokinetics of Diltiazem and Its Metabolites and Effect of Multiple Dose Charcoal Therapy," J Toxicol Clin Toxicol, 1991, 29(1):45-52.

Snover SW and Bocchino V, "Massive Diltiazem Overdose," Ann Emerg Med, 1986, 15(10):1221-4.