Cordarone X 200 150mg/3ml Injection

Where rapid response is required in the control of tachydysrhythmias associated with Wolff-Parkinson-White-syndrome and other types of tachydysrhythmias of paroxysmal nature including supraventricular, nodal and ventricular tachycardias, atrial flutter and atrial fibrillation and ventricular fibrillation which have proved to be resistant to other antidysrhythmic therapy.

Cardiopulmonary resuscitation in the event of cardiac arrest in adults, caused by ventricular fibrillation resistant to external electric shock.

Posology:

Compatibility: Only 5 % dextrose should be used (see section 6.2).

General: CORDARONE X INTRAVENOUS should only be used when facilities exist for cardiac monitoring or defibrillation, should the need arise (see section 4.4).

Intravenous infusion: The standard recommended dose is 5 mg/kg body mass given by intravenous infusion over a period of 20 minutes to 2 hours. Where possible this should be administered as a dilute solution in 250 ml of 5 % dextrose. This may be followed by repeat infusions up to 1200 mg (approximately 15 mg/kg body mass) in up to 500 ml of 5 % dextrose per 24 hours, the rate of infusion being adjusted on the basis of clinical response. When given by infusion, CORDARONE X INTRAVENOUS may reduce drop size and, if appropriate, adjustments should be made to the rate of infusion.

Intravenous injection: CORDARONE X INTRAVENOUS may, at the discretion of the clinician, be given as a bolus injection of 150 mg u2013 300 mg in 10 u2013 20 ml over a minimum of 3 minutes. This should not be repeated for at least 15 minutes. Patients treated in this way must be closely monitored, e.g. in an intensive care unit (see section 4.3).

Cardiopulmonary resuscitation of electro-shock resistant ventricular fibrillation: In the specific case of cardio-pulmonary resuscitation of electro-shock resistant ventricular fibrillation, a first dose of 300 mg diluted in 20 ml of 5 % dextrose solution (or 5 mg/kg of estimated body weight diluted in 30 ml of 5 % dextrose). CORDARONE X INTRAVENOUS is administered via bolus IV injection. An additional 150 mg (or 2,5 mg/kg) IV dose may be considered if the ventricular fibrillation persists.

Maintenance therapy: Oral therapy should be initiated concomitantly at the usual loading dose as soon as possible after an adequate response is obtained and the intravenous therapy gradually phased out. Repeated or continuous infusion via peripheral veins may lead to local discomfort and inflammation. When repeated or continuous infusion is anticipated, administration by a central venous catheter is recommended.

Use in the elderly: It is important that the minimum effective dose is used. Whilst there is no evidence that dosage requirements are different for this group of patients, they may be more susceptible to bradycardia and conduction defects if too high a dose is employed.

• Known hypersensitivity to iodine (one 3 ml ampoule contains approximately 56 mg iodine), to amiodarone or to any of the excipients of CORDARONE X INTRAVENOUS
• Sinus bradycardia, sinoatrial heart block and sick sinus syndrome (risk of sinus arrest), severe atrioventricular conduction disorders, unless a pacemaker is fitted
• Bifascicular or trifascicular disorders, unless a permanent pacemaker is fitted or, unless the patient is in a special care unit and CORDARONE X INTRAVENOUS is used under the cover of electrosystolic pacing
• Combined therapy with medicines which may induce Torsade de Pointes (see section 4.5)
• Severe respiratory failure, circulatory collapse and severe arterial hypotension
• Congestive heart failure when using CORDARONE X INTRAVENOUS as a bolus injection
• Intravenous injection in case of hypotension, myocardiopathy or heart failure (possible worsening)
• Prophylactic use in the preoperative period of cardio-pulmonary surgery
• Thyroid dysfunction (see section 4.4)
• Pregnancy (see section 4.6)
• Lactation (see section 4.6)

The above contraindications do not apply when CORDARONE X INTRAVENOUS is used in the emergency treatment of cardiopulmonary resuscitation of shock (defibrillator) resistant ventricular fibrillation.

Paediatric Patients: The safety and efficacy of CORDARONE X INTRAVENOUS in paediatric patients have not been established. Therefore, its use in paediatric patients is not recommended. The ampoules of CORDARONE X INTRAVENOUS contain benzyl alcohol (see section 4.4). There have been reports of fatal u201cgasping syndromeu201d in neonates (children less than one month of age) following the administration of intravenous solutions containing benzyl alcohol. Symptoms include a striking onset of gasping syndrome, hypotension, bradycardia, and cardio-vascular collapse.

Intravenous bolus injection is not advised because of haemodynamic risks (severe hypotension; circulatory collapse); intravenous infusion is preferable whenever possible. Intravenous bolus injection is to be done only in an emergency where alternative therapies have failed and only in a heart intensive care unit under continuous monitoring (ECG, blood pressure). Dosage is approximately 5 mg/kg body-weight. Except for cases of cardiopulmonary resuscitation of electro-shock resistant ventricular fibrillation, CORDARONE X INTRAVENOUS should be injected over a minimum period of 3 minutes. Intravenous injection should not be repeated less than 15 minutes following the first injection even if the latter was only one ampoule (possible irreversible collapse). Do not mix other preparations in the same syringe. Do not inject other preparations in the same line. Where the treatment should be continued, continue with intravenous infusion (see section 4.2).

CORDARONE X INTRAVENOUS 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 10-17 % in some series of patients with ventricular dysrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of some patients. Pulmonary toxicity has been fatal about 10 % of the time. Liver injury is common with CORDARONE X INTRAVENOUS, 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. CORDARONE X INTRAVENOUS can exacerbate the dysrhythmias e.g. by making the dysrhythmias less well-tolerated or more difficult to reverse. This has occurred in 2-5 % of patients in various series, and significant heart block or sinus bradycardia has been seen in 2-5 %. Due to the long elimination half-life of CORDARONE X INTRAVENOUS, the risk of prodysrhythmic effects is prolonged after amiodarone is stopped. Even in patients at high risk of dysrhythmic death, in whom the toxicity of CORDARONE X INTRAVENOUS is an acceptable risk, CORDARONE X INTRAVENOUS 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 utilise alternative medicines first.

CORDARONE X INTRAVENOUS should be avoided in patients with porphyria as it may precipitate an attack.

Intravenous administration: CORDARONE X INTRAVENOUS should only be used in a special care unit under continuous monitoring (ECG, blood pressure). To avoid injection site reactions, CORDARONE X INTRAVENOUS should, whenever possible, be administrated through a central venous line.

Thyroid hormone abnormalities: Both hyper- and hypothyroidism have occurred commonly during, or soon after, treatment with CORDARONE X INTRAVENOUS. Simple monitoring of the usual biochemical tests is confusing because some (PBI and 131 I uptake) are invalidated and others (T 4 , T 3 and FTI) may be altered where the patient is clearly euthyroid. Clinical monitoring is therefore recommended and should be continued for some months after discontinuation of CORDARONE X INTRAVENOUS treatment. This is particularly important in the elderly. In patients whose history indicates an increased risk of thyroid dysfunction, regular testing is recommended.

Hyperthyroidism: Clinical features of hyperthyroidism such as weight loss, asthenia, restlessness, increase in heart rate or a recurrence of the cardiac dysrhythmia, angina or congestive heart failure, should alert the clinician. The diagnosis may be supported by the finding of an elevated serum tri-iodothyronine (T 3 ), a low level of thyroid stimulating hormone (TSH as measured by high sensitivity methods) and a reduced TSH response to thyrotrophin releasing hormone (TRH). Elevation of reverse T3(rT3) may also be found. In the case of hyperthyroidism CORDARONE X INTRAVENOUS therapy should be withdrawn. Courses of anti-thyroid medication have been used for the treatment of severe thyroid hyperactivity; large doses may be required initially. These may not always be effective and concomitant high dose corticosteroid therapy may be required for several weeks.

Hypothyroidism: The clinical features of hypothyroidism such as weight gain and reduced activity or excessive bradycardia should alert the clinician. The onset may be abrupt. The diagnosis may be supported by the presence of an elevated serum TSH level and an exaggerated TSH response to TRH. The thyroxine (T4), T3 and free thyroxine index (FTI) may be low. Thyroid hypofunction usually resolves within 3 months of cessation of CORDARONE X INTRAVENOUS; it may be treated cautiously with L-thyroxine. Concomitant use of CORDARONE X INTRAVENOUS should only be used in life-threatening situations, when TSH levels may provide a guide to L-thyroxine dosage.

Eye disorders (see section 4.8): If blurred or decreased vision occurs, complete ophthalmologic examination including fundoscopy should be promptly performed. Appearance of optic neuropathy and/or optic neuritis requires CORDARONE X INTRAVENOUS withdrawal due to the potential progression to blindness.

Cardiac disorders: Onsets of new dysrhythmias or worsening of treated dysrhythmias, sometimes fatal, have been reported. It is important, but difficult, to differentiate a lack of efficacy of the medicine from a pro-dysrhythmic effect, whether or not this is associated with a worsening of the cardiac condition. The pro-dysrhythmic effect of CORDARONE X INTRAVENOUS may occur alone or in combination with other QT prolonging factors, particularly other anti-dysrhythmic medicines, digoxin and hypokalaemia (see section 4.5). These effects are more rarely reported than with most of the other anti-dysrhythmic medicines and they generally occur in the case of certain medicine interactions or electrolytic disorders. Despite QT interval prolongation, CORDARONE X INTRAVENOUS exhibits low torsadogenic activity (see section 4.5 and 4.8). Latent or manifest heart failure may be worsened by CORDARONE X INTRAVENOUS. In this case, CORDARONE X INTRAVENOUS should be associated with the usual cardiotonic and diuretic treatments. CORDARONE X INTRAVENOUS may lead to severe bradycardia and to conduction disturbances with the appearance of an idioventricular rhythm, particularly in elderly patients or during digoxin therapy. In these circumstances CORDARONE X INTRAVENOUS treatment should be withdrawn. If necessary, beta-adrenostimulants or glucagon may be given.

Concomitant use of CORDARONE X INTRAVENOUS is not recommended with the following medicines: beta-blockers, heart rate lowering calcium channel inhibitors (verapamil, diltiazem), stimulating laxative agents which may cause hypokalaemia (see section 4.3 and 4.5).

Before surgery, the anaesthetist should be informed that the patient is taking CORDARONE X INTRAVENOUS (see section 4.5).

Benzyl alcohol: CORDARONE X INTRAVENOUS contains 60 mg benzyl alcohol per 3 ml ampoule, which is equivalent to 20 mg/ml. Benzyl alcohol may cause allergic reactions (see section 2). Benzyl alcohol has been linked with the risk of severe side effects, including breathing problems called u201cgasping syndromeu201d in young children (see section 4.3). High volumes should be used with caution and only if necessary, especially in patients with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

PHARMACODYNAMIC INTERACTIONS: Medicines inducing Torsade de Pointes or prolonging QT:

• Medicines inducing Torsade de Pointes, which may be fatal: The risk of Torsade de pointes may be increased when CORDARONE X INTRAVENOUS is used in combination with other medicines which directly or indirectly prolong the QT interval.

Combined therapy with medicines that may induce Torsade de Pointes is contraindicated (see section 4.3), including:

• Antidysrhythmic medicines such as Class Ia, sotalol, bepridil, disopyramide, quinidine.
• Non-antidysrhythmic medicines such as vincamine, some neuroleptic medicines, cisapride, erythromycin IV, pentamidine (when administered parenterally).
• Concomitant administration with dysrhythmogenic medicines for example phenothiazine antipsychotics.
• Certain antihistamines such as mizolastine.
• Antimalarials such as quinine, mefloquine, chloroquine, halofantrine.
• Lithium and tricyclic antidepressants such as doxepin, maprotiline, amitriptyline.

Medicines prolonging QT: Co-administration of CORDARONE X INTRAVENOUS with medicines known to prolong the QT interval must be based on a careful assessment of the potential risks and benefits for each patient since the risk of Torsade de Pointes may increase and patients should be monitored for QT prolongation. Fluoroquinolones should be avoided in patients receiving CORDARONE X INTRAVENOUS (e.g. moxifloxacin, ciprofloxacin).

Medicines lowering heart rate or causing automaticity or conduction disorders: Combined therapy with the following medicines is not recommended: Beta-blockers and heart rate lowering calcium channel inhibitors (verapamil, diltiazem) as automaticity (excessive bradycardia) and conduction disorders may occur.

Medicines which may induce hypokalaemia: Combined therapy with the following medicines is not recommended: Stimulating laxative medicines which may cause hypokalaemia such as senna and bisacodyl thus increasing the risk of Torsade de Pointes; other types of laxatives should be used.

Caution should be exercised when using the following medicines in combination with CORDARONE X INTRAVENOUS:

• Diuretics inducing hypokalaemia, either alone or combined.
• Systemic corticosteroids (gluco-, mineralo-), adrenocorticotrophic hormone (ACTH).
• Amphotericin B (IV).

It is necessary to prevent the onset of hypokalaemia (and to correct hypokalaemia); the QT interval should be monitored and, in case of Torsade de Pointes, antidysrhythmic medicines should not be given (ventricular pacing should be initiated; IV magnesium may be used).

General anaesthesia (see section 4.4): Potentially severe complications have been reported in patients receiving CORDARONE X INTRAVENOUS, undergoing general anaesthesia: bradycardia (unresponsive to atropine), hypotension, disturbances of conduction, decreased cardiac output. Cases of severe respiratory complications (adult acute respiratory distress syndrome), sometimes fatal, have been observed usually in the period immediately following surgery. A possible interaction with a high oxygen concentration may be implicated.

Pregnancy: In view of amiodaroneu2019s effect on the foetal thyroid gland, CORDARONE X INTRAVENOUS is contraindicated during pregnancy.

Breastfeeding: CORDARONE X INTRAVENOUS is excreted into the breastmilk in significant quantities and breastfeeding is contraindicated (see section 4.3).

Driving or operating machinery should be carried out with caution because CORDARONE X INTRAVENOUS causes blurred vision and coloured halos in dazzling light.

The following adverse reactions are classified by system organ class and ranked under heading of frequency using the following convention: very common (u2265 10 %), common (u2265 1 % and < 10 %), uncommon (u2265 0,1 % and < 1 %), rare (u2265 0,01 % and < 0,1 %), very rare (< 0,01 %), unknown (cannot be estimated from available data).

Immune system disorders: Very rare: anaphylactic shock

Blood and lymphatic system disorders: Very rare: haemolytic anaemia, aplastic anaemia and thrombocytopenia

Endocrine disorders: Common: hypothyroidism and hyperthyroidism, sometimes fatal. Very rare: Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Nervous system disorders: Very rare: benign intracranial hypertension, nightmare, headaches, vertigo and sleeplessness

Cardiac disorders: Common: bradycardia, generally dose-related. ECG changes, i.e. QT interval lengthening corresponding to prolonged repolarisation; U-waves and deformed T-waves may occur. Uncommon: conduction disturbances (sinoatrial block, AV block of various degrees). Very rare: marked bradycardia or sinus arrest in patients with sinus node dysfunction and/or in elderly patients. Onset of new dysrhythmia or worsening of existing dysrhythmia, sometimes followed cardiac arrest (see section 4.4)

Vascular disorders: Common: decrease in blood pressure, usually moderate and transient. Cases of hypotension or collapse have been reported following overdosage or a too rapid injection (see section 4.2). Very rare: temporary hot flushes

Gastrointestinal disorders: Very rare: nausea, vomiting and metallic taste

General disorders and administration site conditions: Common: local inflammation of veins following intravenous infusion may be avoided by the use of a central venous catheter. Injection site reactions such as pain, erythema, oedema, necrosis, extravasation, infiltration, inflammation, induration, thrombophlebitis, phlebitis, cellulitis, infection, pigmentation changes

Hepato-biliary disorders: Very rare: isolated increases in serum transaminases, which is usually moderate (1,5 to 3 times normal range) occurring at the beginning of therapy. It may return to normal with dose reduction or even spontaneously. Acute liver disorders with high serum transaminases and/or cholestasis with jaundice including hepatic failure, sometimes fatal (see section 4.4)

Post-marketing data: Blood and lymphatic system disorders: neutropenia, agranulocytosis. Immune system disorders: angioedema (Quinckeu2019s Oedema). Psychiatric disorders: confusional state/delirium, hallucination. Eye disorders: optic neuropathy/neuritis that may progress to blindness. Cardiac disorders: Torsade de Pointes (see section 4.4 and 4.5). Gastrointestinal disorders: pancreatitis/ acute pancreatitis. Skin and subcutaneous tissue disorders: urticaria, eczema, severe skin reactions sometimes fatal including Toxic Epidermal Necrolysis (TEN)/Stevens-Johnson syndrome (SJS), bullous dermatitis, Drug reaction with Eosinophilia and Systematic Symptoms (DRESS) (see section 4.4). Musculoskeletal and connective tissue disorders: back pain. Reproductive system and breast disorders: libido decreased. Injury, poisoning and procedural complications: primary graft dysfunction post cardiac transplant (section 4.4)

Overdosage may lead to severe bradycardia and to conduction disturbances with the appearance of an idioventricular rhythm, particularly in the elderly patients or during digoxin therapy. In these circumstances, CORDARONE X INTRAVENOUS treatment should be withdrawn. In the event of an overdosage general supportive measures should be employed. The patient should be monitored and if bradycardia ensues beta-adrenostimulants or glucagon may be given. Spontaneously resolving attacks of ventricular tachycardia may also occur. Due to the pharmacokinetics of CORDARONE X INTRAVENOUS, adequate and prolonged surveillance of the patient, particularly cardiac status, is recommended.