Ethmozine

• Shire US Inc.

Ethmozine® at daily doses of 600-900 mg produces a dose-related reduction in the occurrence of frequent ventricular premature depolarizations (VPDs) and reduces the incidence of nonsustained and sustained ventricular tachycardia (VT). In controlled clinical trials, Ethmozine® has been shown to have antiarrhythmic activity that is generally similar to that of disopyramide, propranolol and quinidine at the doses studied. In controlled and compassionate use programmed electrical stimulation studies (PES), Ethmozine® prevented the induction of sustained ventricular tachycardia in approximately 25% (19/75) of patients. In a post-marketing randomized comparative PES study, Ethmozine® had a response rate of approximately 12% (7/59). Activity of Ethmozine® is maintained during long-term use.

Ethmozine® is effective in treating ventricular arrhythmias in patients with and without organic heart disease. Ethmozine® may be effective in patients in whom other antiarrhythmic agents are ineffective, not tolerated and/or contraindicated.

Arrhythmia exacerbation or "rebound" is not noted following discontinuation of Ethmozine® therapy.

Ethmozine® is indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that, in the judgement of the physician are life-threatening. Because of the proarrhythmic effects of Ethmozine®, its use with lesser arrhythmias is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided.

Initiation of Ethmozine® treatment, as with other antiarrhythmic agents used to treat life-threatening arrhythmias, should be carried out in the hospital. Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias.

General:

Ethmozine® slows AV nodal and intraventricular conduction, producing dose-related increases in the PR and QRS intervals. In clinical trials, the average increase in the PR interval was 12% and the QRS interval was 14%. Although the QTC interval was increased, this is wholly because of QRS prolongation; the JT interval is shortened, indicating the absence of significant slowing of ventricular repolarization. The degree of lengthening of PR and QRS intervals does not predict efficacy.

In controlled clinical trials and in open studies, the overall incidence of delayed ventricular conduction, including new bundle branch block pattern, was approximately 9.4%. In patients without baseline conduction abnormalities, the frequency of second-degree AV block was 0.2% and third-degree AV block did not occur. In patients with baseline conduction abnormalities, the frequencies of second-degree AV block and third-degree AV block were 0.9% and 1.4%, respectively.

Ethmozine® therapy was discontinued in 1.6% of patients due to electrocardiographic changes (0.6% due to sinus pause or asystole, 0.2% to AV block, 0.2% to junctional rhythm, 0.4% to intraventricular conduction delay, and 0.2% to wide QRS and/or PR interval).

In patients with pre-existing conduction abnormalities, Ethmozine® therapy should be initiated cautiously. If second- or third-degree AV block occurs, Ethmozine® therapy should be discontinued unless a ventricular pacemaker is in place. When changing the dose of Ethmozine® or adding concomitant medications which may also affect cardiac conduction, patients should be monitored electrocardiographically.

Patients with significant liver dysfunction have reduced plasma clearance and an increased half-life of Ethmozine®. Although the precise relationship of Ethmozine® levels to effect is not clear, patients with hepatic disease should be treated with lower doses and closely monitored for excessive pharmacological effects, including effects on ECG intervals, before dosage adjustment. Patients with severe liver disease should be administered Ethmozine® with particular care, if at all (see DOSAGE AND ADMINISTRATION).

Plasma levels of intact Ethmozine® are unchanged in hemodialysis patients, but a significant portion (39%) of Ethmozine® is metabolized and excreted in the urine. Although no identified active metabolite is known to increase in people with renal failure, metabolites of unrecognized importance could be affected. For this reason, Ethmozine® should be administered cautiously in patients with impaired renal function. Patients with significant renal dysfunction should be started on lower doses and monitored for excessive pharmacologic effects, including ECG intervals, before dosage adjustment (see DOSAGE AND ADMINISTRATION).

Most patients with congestive heart failure have tolerated the recommended Ethmozine® daily doses without unusual toxicity or change in effect. Pharmacokinetic differences between Ethmozine® patients with and without congestive heart failure were not apparent (See Hepatic Impairment above). In some cases, worsened heart failure has been attributed to Ethmozine®. Patients with pre-existing heart failure should be monitored carefully when Ethmozine® is initiated.

The effect of Ethmozine® on the sensing and pacing thresholds of artificial pacemakers has not been sufficiently studied. In such patients, pacing parameters must be monitored, if Ethmozine® is used.

Drug Interactions

No significant changes in serum digoxin levels or pharmacokinetics have been observed in patients or healthy subjects receiving concomitant Ethmozine® therapy. Concomitant use was associated with additive prolongation of the PR interval, but not with a significant increase in the rate of second- or third-degree AV block.

Concomitant administration of cimetidine resulted in a decrease in Ethmozine® clearance of 49% and a 1.4 fold increase in plasma levels in healthy subjects. During clinical trials, no significant changes in the efficacy or tolerance of Ethmozine® have been observed in patients receiving concomitant cimetidine therapy. Patients on cimetidine should have Ethmozine® therapy initiated at relatively low doses, not more than 600 mg/day. Patients should be monitored when concomitant cimetidine therapy is instituted or discontinued or when the Ethmozine® dose is changed.

Concomitant administration of beta blacker therapy did not reveal significant changes in overall electrocardiographic intervals in patients. In one controlled study, Ethmozine® (moricizine hydrochloride) and propranolol administered concomitantly produced a small additive increase in the PR interval.

Theophylline clearance and plasma half-life were significantly affected by multiple dose Ethmozine® administration when both conventional and sustained release theophylline were given to healthy subjects (clearance increased 44-66% and plasma half-life decreased 19-33%). Plasma theophylline levels should be monitored when concomitant Ethmozine® is initiated or discontinued.

Because of possible additive pharmacologic effects, caution is indicated when Ethmozine® is used with any drug that affects cardiac electrophysiology. Uncontrolled experience in patients indicates no serious adverse interaction during the concomitant use of Ethmozine® and diuretics, vasodilators, antihypertensive drugs, calcium channel blockers, beta blockers, angiotensin-converting enzyme inhibitors, or warfarin. Plasma warfarin levels, warfarin pharmacokinetics, and prothrombin times were unaffected during multiple dose Ethmozine® administration to young, healthy, male subjects in a controlled study. However, there are isolated reports of the need to either increase or decrease warfarin doses after initiation of Ethmozine®. Some patients who were taking warfarin with a stable prothrombin time experienced excessive prolongation of the prothrombin time following the initiation of Ethmozine®. In some cases, liver enzymes also were elevated. Bleeding or bruising may occur. When Ethmozine® is started or stopped in a patient stabilized on warfarin, more frequent prothrombin time monitoring is advisable.

Results from in vitro studies do not suggest alterations in Ethmozine® plasma protein binding in the presence of other highly plasma protein bound drugs.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

In a 24-month mouse study in which Ethmozine® was administered in the feed at concentrations calculated to provide doses ranging up to 320 mg/kg/day, ovarian tubular adenomas and granulosa cell tumors were limited in occurrence to Ethmozine® treated animals. Although the findings were of borderline statistical significance, or not statistically significant, historical control data indicate that both of these tumors are uncommon in the strain of mouse studied.

In a 24-month mouse study in which Ethmozine® was administered by gavage to rats at doses of 25, 50 and 100 mg/kg/day, Zymbal's Gland Carcinoma was observed in one mid-dose and two high-dose males. This tumor appears to be uncommon in the strain of rat studied. Rats of both sexes showed a dose-related increase in hepatocellular cholangioma (also described as bile ductile cystadenoma or cystic hyperplasia) along with fatty metamorphosis, possibly due to disruption of hepatic choline utilization for phospholipid biosynthesis. The rat is known to be uniquely sensitive to alteration in choline metabolism.

Ethmozine® was not mutagenic when assayed for genotoxicity in in vitro bacterial (Ames test) and mammalian (Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase and sister chromatid exchange) cell systems or in in vivo mammalian systems (rate bone cytogenicity and mouse micronucleus).

A general reproduction and fertility study was conducted in rats at dose levels up to 6.7 times the maximum recommended human dose of 900 mg/day (based upon 50 kg human body weight) and revealed no evidence of impaired male or female fertility.

Pregnancy

Teratology studies have been performed with Ethmozine® in rats and in rabbits at doses up to 6.7 and 4.7 times the maximum recommended human daily dose, respectively, and have revealed no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Ethmozine® should be used during pregnancy only if clearly needed.

In a study in which rats were dosed with Ethmozine® prior to mating, during mating and throughout gestation and lactation, dose levels 3.4 and 6.7 times the maximum recommended human daily dose produced a dose-related decrease in pup and maternal weight gain, possibly related to a larger litter size. In a study in which dosing was begun on Day 15 of gestation, Ethmozine®, at a level 6.7 times the maximum recommended human daily dose, produced a retardation in maternal weight gain but no effect on pup growth.

Ethmozine® is secreted in the milk of laboratory animals and has been reported to be present in human milk. Because of the potential for serious adverse reactions in nursing infants from Ethmozine®, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Ethmozine® in children less than 18 years of age have not been established.

The most serious adverse reaction reported for Ethmozine® is proarrhythmia (see WARNINGS). This occurred in 3.7% of 1072 patients with ventricular arrhythmias who received a wide range of doses under a variety of circumstances.

In addition to discontinuations because of proarrhythmias, in controlled clinical trials and in open studies, adverse reactions led to discontinuation of Ethmozine® in 7% of 1105 patients with ventricular and supraventricular arrhythmias, including 3.2% due to nausea, 1.6% due to ECG abnormalities (principally conduction defects, sinus pause, junctional rhythm, or AV block), 1% due to congestive heart failure and 0.3-0.4% due to dizziness, anxiety, drug fever, urinary retention, blurred vision, gastrointestinal upset, rash, and laboratory abnormalities.

The most frequently occurring adverse reactions in the 1072 patients (including all adverse experiences whether or not considered Ethmozine®-related by the investigator) were dizziness (15.1%), nausea (9.6%), headache (8.0%), fatigue (5.9%), palpitations (5.8%) and dyspnea (5.7%). Dizziness appears to be related to the size of each dose. In a comparison of 900 mg/day given at 450 mg b.i.d. or 300 mg t.i.d., more than 20% of patients experienced dizziness on the b.i.d. regimen vs. 12% on the t.i.d. regimen.

Adverse reactions reported by less than 5%, but in 2% or greater of the patients were: sustained ventricular tachycardia, hypesthesias, abdominal pain, dyspepsia, vomiting, sweating, cardiac chest pain, asthenia, nervousness, paresthesias, congestive heart failure, muscoloskeletal pain, diarrhea, dry mouth, cardiac death, sleep disorders and blurred vision.

Adverse reactions infrequently reported (in less than 2% of the patients) were:

Cardiovascular hypotension, hypertension, syncope, supraventricular arrhythmias (including atrial fibrillation/flutter), cardiac arrest, bradycardia, pulmonary embolism, myocardial infarction, vasodilation, cerebrovascular events, thrombophiebitis;

Nervous System tremor, anxiety, depression, euphoria, confusion, somnolence, agitation, seizure, coma, abnormal gait, hallucinations, nystagmus, diplopia, speech disorder, akathisia, loss of memory, ataxia, abnormal coordination, dyskinesia, vertigo, tinnitus;

Genitourinary urinary retention or frequency, dysuria, urinary incontinence, kidney pain, impotence, decreased libido;

Respiratory hyperventilation, apnea, asthma, pharyngitis, cough, sinusitis;

Gastrointestinal anorexia, bitter taste, dysphagia, flatulence, ileus;

Other drug fever, hypothermia, temperature intolerance, eye pain, rash, pruritus, dry skin, urticaria, swelling of the lips and tongue, perorbital edema.

During Ethmozine® therapy, two patients developed thrombocytopenia that may have been drug-related. Clinically significant elevations in liver function tests (bilirubin, serum transaminases) and jaundice consistent with hepatitis were rarely reported. Although a cause and effect relationship has not been established, caution is advised in patients who develop unexplained signs of hepatic dysfunction, and consideration should be given to discontinuing therapy.

Three patients developed rechallenge-confirmed drug fever, with one patient experiencing an elevation above 103°F (to 105°F, with rigors). Fevers occurred at about 2 weeks in 2 cases, and after 21 weeks in the third. Fevers resolved within 48 hours of discontinuation of moricizine.

Adverse reactions were generally similar in patients over 65 (n=375) and under 65 (n=697), although discontinuation of therapy for reasons other than proarrhythmia was more common in older patients (13.9% vs. 7.7%). Overall mortality was greater in older patients (9.3% vs. 3.9%), but those were not deaths attributed to treatment and the older patients had more serious underlying heart disease.

The following table compares the most common (occurrence in more than 2% of the patients) non-cardiac adverse reactions (i.e. drug-related or of unknown relationship) in controlled clinical trials during the first one to two weeks of therapy with Ethmozine®, quinidine, placebo, disopyramide or propranolol in patients with ventricular arrhythmias.

Deaths have occurred after accidental or intentional overdosages of 2,250 and 10,000 mg of Ethmozine® (moricizine hydrochloride), respectively.

Signs, Symptoms and Laboratory Findings Associated with an Overdosage of Drug

Overdosage with Ethmozine® may produce emesis, lethargy, coma, syncope, hypotension, conduction disturbances, exacerbation of congestive heart failure, myocardial infarction, sinus arrest, arrhythmias (including junctional bradycardia, ventricular tachycardia, ventricular fibrillation and asystole), and respiratory failure.

Lethal Dose in Animals

Oral doses of Ethmozine® of about 200 mg/kg in dogs, 250 mg/kg in monkeys, 420 mg/kg in mice and 905 mg/kg in rats were lethal to about one-half of the animals exposed. Death was usually preceded by tremors, convulsions and respiratory depression.

Recommended General Treatment Procedures

A specific antidote for Ethmozine® has not been identified. In the event of overdosage, treatment should be supportive. Patients should be hospitalized and monitored for cardiac, respiratory and CNS changes. Advanced life support systems, including an intracardiac pacing catheter, should be provided where necessary. Acute overdosage should be treated with appropriate gastric evacuation, and with special care to avoid aspiration. Accidental introduction of Ethmozine® into the lungs of monkeys resulted in rapid arrhythmic death.