TAMBOCOR (Page 3 of 4)

PRECAUTIONS:

Drug Interactions. TAMBOCOR has been administered to patients receiving digitalis preparations or beta-adrenergic blocking agents without adverse effects. During administration of multiple oral doses of TAMBOCOR to healthy subjects stabilized on a maintenance dose of digoxin , a 13% — 19% increase in plasma digoxin levels occurred at six hours postdose.

In a study involving healthy subjects receiving TAMBOCOR and propranolol concurrently, plasma flecainide levels were increased about 20% and propranolol levels were increased about 30% compared to control values. In this formal interaction study, TAMBOCOR and propranolol were each found to have negative inotropic effects; when the drugs were administered together, the effects were additive. The effects of concomitant administration of TAMBOCOR and propranolol on the PR interval were less than additive. In TAMBOCOR clinical trials, patients who were receiving beta blockers concurrently did not experience an increased incidence of side effects. Nevertheless, the possibility of additive negative inotropic effects of beta blockers and flecainide should be recognized.

Flecainide is not extensively bound to plasma proteins. In vitro studies with several drugs which may be administered concomitantly showed that the extent of flecainide binding to human plasma proteins is either unchanged or only slightly less. Consequently, interactions with other drugs which are highly protein bound (e.g., anticoagulants) would not be expected. TAMBOCOR has been used in a large number of patients receiving diuretics without apparent interaction. Limited data in patients receiving known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate only a 30% increase in the rate of flecainide elimination. In healthy subjects receiving cimetidine (1 gm daily) for one week, plasma flecainide levels increased by about 30% and half-life increased by about 10%.

When amiodarone is added to flecainide therapy, plasma flecainide levels may increase two-fold or more in some patients, if flecainide dosage is not reduced. (See Dosage and Administration.)

Drugs that inhibit cytochrome P450IID6, such as quinidine , might increase the plasma concentrations of flecainide in patients that are on chronic flecainide therapy; especially if these patients are extensive metabolizers.

There has been little experience with the coadministration of TAMBOCOR and either disopyramide or verapamil. Because both of these drugs have negative inotropic properties and the effects of coadministration with TAMBOCOR are unknown, neither disopyramide nor verapamil should be administered concurrently with TAMBOCOR unless, in the judgment of the physician, the benefits of this combination outweigh the risks. There has been too little experience with the coadministration of TAMBOCOR with nifedipine or diltiazem to recommend concomitant use.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies with flecainide in rats and mice at doses up to 60 mg/kg/day have not revealed any compound-related carcinogenic effects. Mutagenicity studies (Ames test, mouse lymphoma and in vivo cytogenetics) did not reveal any mutagenic effects. A rat reproduction study at doses up to 50 mg/kg/day (seven times the usual human dose) did not reveal any adverse effect on male or female fertility.

Pregnancy. Pregnancy Category C. Flecainide has been shown to have teratogenic effects (club paws, sternebrae and vertebrae abnormalities, pale hearts with contracted ventricular septum) and an embryotoxic effect (increased resorptions) in one breed of rabbit (New Zealand White) when given doses of 30 and 35 mg/kg/day, but not in another breed of rabbit (Dutch Belted) when given doses up to 30 mg/kg/day. No teratogenic effects were observed in rats and mice given doses up to 50 and 80 mg/kg/day, respectively; however, delayed sternebral and vertebral ossification was observed at the high dose in rats. Because there are no adequate and well-controlled studies in pregnant women, TAMBOCOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery. It is not known whether the use of TAMBOCOR during labor or delivery has immediate or delayed adverse effects on the mother or fetus, affects the duration of labor or delivery, or increases the possibility of forceps delivery or other obstetrical intervention.

Nursing Mothers. Results from a multiple dose study conducted in mothers soon after delivery indicates that flecainide is excreted in human breast milk in concentrations as high as 4 times (with average levels about 2.5 times) corresponding plasma levels; assuming a maternal plasma level at the top of the therapeutic range (1 μg/mL), the calculated daily dose to a nursing infant (assuming about 700 mL breast milk over 24 hours) would be less than 3 mg.

Pediatric Use. The safety and efficacy of TAMBOCOR in the fetus, infant, or child have not been established in double-blind, randomized, placebo-controlled trials (see CLINICAL PHARMACOLOGY,WARNINGS, and DOSAGE AND ADMINISTRATION).

Hepatic Impairment. Since flecainide elimination from plasma can be markedly slower in patients with significant hepatic impairment, TAMBOCOR should not be used in such patients unless the potential benefits clearly outweigh the risks. If used, frequent and early plasma level monitoring is required to guide dosage (see Plasma Level Monitoring); dosage increases should be made very cautiously when plasma levels have plateaued (after more than four days).

ADVERSE REACTIONS:

In post-myocardial infarction patients with asymptomatic PVCs and non-sustained ventricular tachycardia, TAMBOCOR therapy was found to be associated with a 5.1% rate of death and non-fatal cardiac arrest, compared with a 2.3% rate in a matched placebo group. (See Warnings.)

Adverse effects reported for TAMBOCOR, described in detail in the Warnings section, were new or worsened arrhythmias which occurred in 1% of 108 patients with PSVT and in 7% of 117 patients with PAF; and new or exacerbated ventricular arrhythmias which occurred in 7% of 1330 patients with PVCs, non-sustained or sustained VT. In patients treated with flecainide for sustained VT, 80% (51/64) of proarrhythmic events occurred within 14 days of the onset of therapy. 198 patients with sustained VT experienced a 13% incidence of new or exacerbated ventricular arrhythmias when dosage was initiated at 200 mg/day with slow upward titration, and did not exceed 300 mg/day in most patients. In some patients, TAMBOCOR treatment has been associated with episodes of unresuscitatable VT or ventricular fibrillation (cardiac arrest). (See Warnings.) New or worsened CHF occurred in 6.3% of 1046 patients with PVCs, non-sustained or sustained VT. Of 297 patients with sustained VT, 9.1% experienced new or worsened CHF. New or worsened CHF was reported in 0.4% of 225 patients with supraventricular arrhythmias. There have also been instances of second- (0.5%) or third-degree (0.4%) AV block. Patients have developed sinus bradycardia, sinus pause, or sinus arrest, about 1.2% altogether (see Warnings). The frequency of most of these serious adverse events probably increases with higher trough plasma levels, especially when these trough levels exceed 1.0 μg/mL.

There have been rare reports of isolated elevations of serum alkaline phosphatase and isolated elevations of serum transaminase levels. These elevations have been asymptomatic and no cause and effect relationship with TAMBOCOR has been established. In foreign postmarketing surveillance studies, there have been rare reports of hepatic dysfunction including reports of cholestasis and hepatic failure, and extremely rare reports of blood dyscrasias. Although no cause and effect relationship has been established, it is advisable to discontinue TAMBOCOR in patients who develop unexplained jaundice or signs of hepatic dysfunction or blood dyscrasias in order to eliminate TAMBOCOR as the possible causative agent.

Incidence figures for other adverse effects in patients with ventricular arrhythmias are based on a multicenter efficacy study, utilizing starting doses of 200 mg/day with gradual upward titration to 400 mg/day. Patients were treated for an average of 4.7 months, with some receiving up to 22 months of therapy. In this trial, 5.4% of patients discontinued due to non-cardiac adverse effects.

Table 1 Most Common Non-Cardiac Adverse Effects in Ventricular Arrhythmia Patients Treated with TAMBOCOR in the Multicenter Study

* Dizziness includes reports of dizziness, lightheadedness, faintness, unsteadiness, near syncope, etc.

† Visual disturbance includes reports of blurred vision, difficulty in focusing, spots before eyes, etc.

Incidence by Dose
During Upward Titration

Incidence
All 429 200 300 400
Adverse Patients at mg/Day mg/Day mg/Day
Effect Any Dose (N=426) (N=293) (N=100)
Dizziness* 18.9% 11.0% 10.6% 13.0%
Visual Disturbances† 15.9% 5.4% 12.3% 18.0%
Dyspnea 10.3% 5.2% 7.5% 4.0%
Headache 9.6% 4.5% 6.1% 9.0%
Nausea 8.9% 4.9% 4.8% 6.0%
Fatigue 7.7% 4.5% 4.4% 3.0%
Palpitation 6.1% 3.5% 2.4% 7.0%
Chest Pain 5.4% 3.1% 3.8% 1.0%
Asthenia 4.9% 2.6% 2.0% 4.0%
Tremor 4.7% 2.4% 3.4% 2.0%
Constipation 4.4% 2.8% 2.1% 1.0%
Edema 3.5% 1.9% 1.4% 2.0%
Abdominal Pain 3.3% 1.9% 2.4% 1.0%

The following additional adverse experiences, possibly related to TAMBOCOR therapy and occurring in 1% to less than 3% of patients, have been reported in acute and chronic studies: Body as a Whole – malaise, fever; Cardiovascular – tachycardia, sinus pause or arrest; Gastrointestinal – vomiting, diarrhea, dyspepsia, anorexia; Skin – rash; Visual – diplopia; Nervous System – hypoesthesia, paresthesia, paresis, ataxia, flushing, increased sweating, vertigo, syncope, somnolence, tinnitus; Psychiatric – anxiety, insomnia, depression.

The following additional adverse experiences, possibly related to TAMBOCOR, have been reported in less than 1% of patients: Body as a Whole – swollen lips, tongue and mouth; arthralgia, bronchospasm, myalgia; Cardiovascular – angina pectoris, second-degree and third-degree AV block, bradycardia, hypertension, hypotension; Gastrointestinal – flatulence; Urinary System – polyuria, urinary retention; Hematologic – leukopenia, granulocytopenia, thrombocytopenia; Skin – urticaria, exfoliative dermatitis, pruritis, alopecia; Visual – eye pain or irritation, photophobia, nystagmus; Nervous System – twitching, weakness, change in taste, dry mouth, convulsions, impotence, speech disorder, stupor, neuropathy; Respiratory – pneumonitis/pulmonary infiltration possibly due to chronic flecainide treatment; Psychiatric – amnesia, confusion, decreased libido, depersonalization, euphoria, morbid dreams, apathy.

For patients with supraventricular arrhythmias, the most commonly reported noncardiac adverse experiences remain consistent with those known for patients treated with TAMBOCOR for ventricular arrhythmias. Dizziness is possibly more frequent in PAF patients.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2020. All Rights Reserved.