Usual Adult Dose for Arrhythmias

IV:
Initial dose: 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen:

• Loading infusions: 150 mg over the first 10 minutes (15 mg/min), followed by 360 mg over the next 6 hours (1 mg/min)
• Maintenance infusion: 540 mg over the remaining 18 hours (0.5 mg/min)

Maintenance dose: After the first 24 hours, continue the maintenance infusion rate of 0.5 mg/min; may increase infusion rate to achieve effective arrhythmia suppression.

• Supplemental infusions: 150 mg over 10 minutes (15 mg/min) for breakthrough episodes of ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT)

Maximum dose: Initial infusion rate: 30 mg/min

Duration of therapy: Until ventricular arrhythmias stabilize (most patients require 48 to 96 hours); maintenance infusion of up to 0.5 mg/min can be continued for up to 3 weeks.

Comments: Mean daily doses greater than 2100 mg for the first 24 hours were associated with increased risk of hypotension.

Use: Initiation of treatment and prophylaxis of frequently recurring VF and hemodynamically unstable VT in patients refractory to other therapy.

ORAL:
Loading dose: 800 to 1600 mg orally per day for 1 to 3 weeks (occasionally longer) until adequate arrhythmia control is achieved or if side effects become prominent, then switch to adjustment dose
Adjustment dose: 600 to 800 mg orally per day for 1 month, then switch to maintenance dose
Maintenance dose: 400 mg orally per day

Comments:

• May be administered once a day; twice a day dosing is recommended for total daily doses of 1000 mg or more or in patients who experience gastrointestinal tolerance.
• Close monitoring is indicated during the loading phase and surrounding any dose adjustments.
• Maintenance dose should be determined according to antiarrhythmic effect as assessed by patient tolerance as well as symptoms, Holter recordings, and/or programmed electrical stimulation; some patients may require up to 600 mg/day while some can be controlled on lower doses.

Use: Treatment of life-threatening recurrent VF or life-threatening recurrent hemodynamically unstable VT in patients refractory to adequate doses of other antiarrhythmics or those intolerant of alternative agents.

Renal Dose Adjustments

No adjustment recommended

Liver Dose Adjustments

No adjustment recommended

If progressive hepatic injury or hepatomegaly occurs or hepatic enzyme levels increase to greater than 3 times normal (or double in a patient with elevated baseline levels): Consider dose reduction or discontinuation.

Dose Adjustments

This drug should be used at the lowest effective dose in order to prevent the occurrence of side effects.

IV to oral transition (infusion duration [assuming 0.5 mg/min infusion]: initial oral daily dose)

• Less than one week: 800 to 1600 mg
• One to three weeks: 600 to 800 mg
• Greater than three weeks: 400 mg

Therapeutic drug range: No well-established relationship exists between drug concentration and therapeutic response; however, concentrations much below 1 mg/L are often ineffective and levels above 2.5 mg/L are usually unnecessary.

Precautions

US BOXED WARNINGS (TABLET): These effects may also be seen with IV administration.

• FATAL TOXICITY: This drug is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Even in patients at high risk of arrhythmic death, in whom the toxicity of this drug is an acceptable risk, this drug poses major management problems that could be life-threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first. The difficulty of using this drug safely and effectively itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15% to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when this drug must be stopped will be made difficult by the gradually, but unpredictably, changing body burden of this drug. A similar problem exists when this drug is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.
• HEPATOTOXICITY: Liver injury is common with this drug, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Obtain baseline and periodic liver transaminases and discontinue or reduce dose if the increase exceeds three times normal, or doubles in a patient with an elevated baseline. Discontinue this drug if the patient experiences signs or symptoms of clinical liver injury.
• PROARRHYTHMIC EFFECTS: Like other antiarrhythmics, this drug can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2% to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2% to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with this drug than with many other agents used in this population, the effects are prolonged when they occur. Initiate this drug in a clinical setting where continuous ECGs and cardiac resuscitation are available.
• PULMONARY TOXICITY: This drug has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10% to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Obtain a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, when treatment with this drug is initiated. Repeat history, physical exam, and chest X-ray every 3 to 6 months.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice: The manufacturer product information should be consulted.

Storage requirements: The manufacturer product information should be consulted.

Reconstitution/preparation techniques: The manufacturer product information should be consulted.

IV compatibility: The manufacturer product information should be consulted.

Monitoring:

• Cardiovascular: ECG and blood pressure
• Endocrine: Thyroid function tests
• Hepatic: Liver function tests
• Metabolic: Baseline serum potassium
• Ocular: Ophthalmic examination, including fundoscopy and slit-lamp examination
• Respiratory: History, physical exam, chest X-ray, and pulmonary function tests, including diffusion capacity

Patient advice:

• Inform patients administering this drug to do so consistently with regard to meals.
• Advise patients to avoid consumption of grapefruit juice during treatment with this drug.
• Instruct patients to avoid sun exposure and use sun-barrier creams or protective clothing.
• Advise patients to moderate alcohol consumption while taking this drug.
• If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.
• Advise patients that most manufacturers of corneal refractive laser surgery devices consider corneal refractive laser surgery contraindicated in patients taking this drug.