Download 4.8. Undesirable effects

Corvert (ibutilide fumarate) 87 microgram/ml, solution for infusion
PSUR Workshare SE/H/PSUR/0035/001
Agreed Core Safety Profile
September 2010
Active Substance: Ibutilide fumarate
Brand Names: CORVERT
Pharmaceutical form(s)/strength: Intravenous solution for injection,
87 micrograms per ml
4.2
Posology and method of administration
Patients weighing 60 kg or more: 1 mg ibutilide fumarate (equals 0.87 mg ibutilide which
corresponds to one 10-ml vial) intravenously administered over 10 minutes.
Patients weighing less than 60 kg: 0.01 mg ibutilide fumarate per kg (equals 0.0087 mg
ibutilide/kg which corresponds to 0.1 ml/kg) intravenously administered over 10 minutes.
If the arrhythmia does not terminate within 10 minutes after the end of the initial infusion, a
second dose may be administered. Additional doses are not recommended because of the risk
of QT interval prolongation. Patients who, after 1 hour or more, have not responded to
treatment with CORVERT may be converted using electrocardioversion.
Ibutilide infusion should be stopped as soon as the presenting arrhythmia is terminated or in
the event of sustained or non-sustained ventricular tachycardia or marked prolongation of the
rate corrected QT interval.
The infusion should not be faster than 10 minutes.
Corvert is not recommended for use in children below 18 due to a lack of data on safety and
efficacy.
Use in Elderly Patients:
The mean age of patients in clinical trials was 65. No age-related differences were observed
in pharmacokinetic, efficacy, or safety parameters for patients less than 65 compared to
patients 65 years and older. Therefore, no dose adjustment is recommended for the elderly.
Use in Patients with Renal Impairment:
For patients with decreased renal function, no dose adjustment is recommended. Less than
10% of the dose of CORVERT is excreted unchanged in the urine. In 285 patients with atrial
fibrillation or atrial flutter who were treated with CORVERT, the clearance of ibutilide was
independent of renal function as measured by estimated creatinine clearance (range 21 to 140
ml/min).
Post-Cardiac Surgery Patients:
The following dosage is recommended in haemodynamically stable patients who experience
atrial fibrillation or atrial flutter 24 hours to 7 days following cardiac surgery.
Patients weighing 60 kg or more: 0. 5 mg ibutilide fumarate (equals 0.44 mg ibutilide which
corresponds to 5 ml) intravenously administered over 10 minutes.
Patients weighing less than 60 kg: 0. 005 mg ibutilide fumarate per kg (equals 0. 0044 mg
ibutilide/kg which corresponds to 0. 05 ml/kg) intravenously administered over 10 minutes.
Corvert (ibutilide fumarate) 87 microgram/ml, solution for infusion
PSUR Workshare SE/H/PSUR/0035/001
If the arrhythmia does not terminate within 10 minutes after completed infusion, a second
dose may be administered.
Treatment Control:
If ventricular arrhythmia arises or is worsened during administration of CORVERT, the
infusion should be stopped immediately (see section 4.4 - Special warnings and special
precautions for use).
4.3. Contraindications
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Hypersensitivity to the active substance or to any of the excipients
CORVERT, solution for infusion should not be given to patients who have previously
demonstrated:
o Polymorphic ventricular tachycardia (e.g. torsades de pointe)
o Symptomatic heart failure
o Prolonged QT interval (> 440 msec)
o Second and third degree AV-block in patients without pacemakers
o Sick sinus syndrome
o Recent myocardial infarction (< 1 month)
o Hypokalemia
o Hypomagnesemia
Concomitant treatment with class I or class III antiarrhythmic agents
Severe hepatic impairment
4.4. Special warnings and precautions for use
CORVERT may induce life-threatening ventricular arrhythmias (torsades de pointe).
Polymorphic tachycardia was seen in about 5% of the patients treated for atrial
fibrillation/flutter in clinical studies. Life-threatening sustained polymorphic
ventricular tachycardia was seen in 1.9% of the treated patients. The polymorphic
ventricular tachycardia may degenerate into ventricular fibrillation. Patients with a
history of congestive heart failure (CHF) or low left ventricular ejection fraction
have a higher risk of developing serious proarrhythmia including sustained
polymorphic ventricular tachycardia (see section 4.3 Contraindications).
In the clinical studies, a higher incidence of monomorphic ventricular tachycardias was seen
in women.
Prior to the start of the treatment, the need for anticoagulant treatment should be decided upon
and possible hypokalemia and hypomagnesemia should be corrected. Digoxin intoxication
should be ruled out prior to treatment (see section 4.5 Interactions with other medicinal
products and other forms of interactions). The cardiac rhythm should be continuously
monitored during the entire infusion period and thereafter for a minimum of 4 hours after the
infusion has been stopped. In those cases where the QTc interval has not returned to baseline,
the cardiac rhythm should be supervised for more than 4 hours. Longer monitoring may be
required if proarrhythmic activity is noted during CORVERT infusion or during the 4 hour
monitoring period. If serious proarrhythmia occurs, this should be evaluated and care should
be taken with the future use of medications which have potential to prolong the QT interval or
cause proarrhythmia.
The treatment should be monitored by personnel having knowledge of arrhythmia diagnostics
and equipment for acute defibrillation must be readily available. Patients who previously have
Corvert (ibutilide fumarate) 87 microgram/ml, solution for infusion
PSUR Workshare SE/H/PSUR/0035/001
had ventricular arrhythmias should be monitored for at least 24 hours. Class I or class III
antiarrhythmics should not be given earlier than 4 hours after the end of the ibutilide infusion
and only if the QTc interval has returned to baseline. The cardiac rhythm in these patients
should be monitored for at least 24 hours.
4.5. Interaction with other medicinal products and other forms of interaction
Although formal interaction studies have not been performed, class I antiarrhythmic drugs
(disopyramide, quinidine, procainamide) and other class III drugs (amiodarone, sotalol and
dofetilide) should not be given concomitantly with CORVERT, within 4 hours, and only if
the QTc interval has returned to baseline because of their potential to prolong refractoriness.
The potential for proarrhythmia may increase with the administration of CORVERT to
patients who are being treated with drugs that prolong the QT interval, such as antipsychotic
drugs (phenothiazines: thioridazine, chlorpromazine and levomepromazine; benzamides:
sulpride, sultopride, amisulpride and tiapride; pimozide: haloperidol; droperidol), tricyclic or
tetracyclic antidepressants, antibiotics (macrolides: erythromycin compounds;
fluroquinolones: pentamidine), some antihistamines (terfenadine and astemizole) and drugs of
the other classes (bepridil; cisapride; diphemanil; halofanrin and mizolastine).
The clinician should assess the risk/benefit ratio of concomitant use of ibutilide fumarate and
the medications listed above and the risk of inducing torsades de pointes.
Supraventricular arrhythmias may mask the cardiotoxicity associated with excessive digoxin
levels. Therefore, it is advisable to be particularly cautious in patients whose plasma digoxin
levels are above or suspected to be above the usual therapeutic range. Concomitant treatment
with CORVERT and digoxin does not affect their individual plasma concentration.
Concomitant treatment with beta-adrenergic blocking agents or with calcium channel
blocking agents does not affect the pharmacokinetics of CORVERT
4.6. Pregnancy and lactation
There are no adequate data for the use of ibutilide in pregnant women.
In one species, the rat, studies have shown embryotoxic and teratogenic effects. However
animal studies are insufficient to conclude (see section 5.3).
In view of the indication, CORVERT should be used during pregnancy when clearly
necessary.
Lactation
The excretion of ibutilide in animal and human milk is unknown. Breast-feeding is therefore
not recommended during treatment by ibutilide.
4.7. Effects on ability to drive and use machines
Not relevant
4.8. Undesirable effects
Proarrhythmias are the most common and serious side-effects. In the clinical studies, 1.9% of
the patients developed a life-threatening sustained polymorphic ventricular tachycardia
(torsades de pointes) requiring acute cardioversion; Non-sustained polymorphic ventricular
Corvert (ibutilide fumarate) 87 microgram/ml, solution for infusion
PSUR Workshare SE/H/PSUR/0035/001
tachycardias were seen in 3.1%. All initial episodes of polymorphic ventricular tachycardia
were seen within 40 minutes from the beginning of treatment.
Patients with a history of congestive heart failure (CHF) or low left ventricular
ejection fraction have a higher risk of developing serious proarrhythmia including
sustained polymorphic ventricular tachycardia.
The following undesirable effects have been observed and reported during treatment with
ibutilide with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10);
uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000), not
known (cannot be estimated form the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness
System Organ Class
Cardiac disorders
Vascular disorders
Renal and Urinary
disorders
Investigations
Frequency
common
Undesirable effects
 Ventricular tachycardia (sustained
polymorphic and monomorphic
ventricular tachycardia, non-sustained
polymorphic and monomorphic
ventricular tachycardia)
 Ventricular extrasystoles
 Atrioventricular block
 Bundle branch block
 Bradycardia
 Supraventricular tachycardia.
Uncommon
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Ventricular fibrillation
Angina pectoris
Atrial fibrillation
Common
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Hypotension
Uncommon
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Hypertension
Vasodilatation
Uncommon
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Acute kidney failure
common
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Electrocardiogram QT prolonged
4.9. Overdose
In the clinical trials, four patients were unintentionally overdosed. The largest dose was
3.4 mg ibutilide fumarate administered over 15 minutes. One patient developed increased
ventricular ectopy and monomorphic ventricular tachycardia, another patient developed AV
block 3rd degree and nonsustained polymorphic ventricular tachycardia, and in the other two
patients no adverse events were seen.
In case of overdosage, the risk of occurrence of proarrhythmic events is therefore increased,
especially in patients with a history of congestive heart failure and/or a decreased ejection
Corvert (ibutilide fumarate) 87 microgram/ml, solution for infusion
PSUR Workshare SE/H/PSUR/0035/001
fraction. The clinical effects of an overdosage with ibutilide could exaggerate the expected
prolongation of repolarization seen in usually clinical doses.
In case of overdosing, symptomatic and supporting therapy should be given