Amiodarone Hydrochloride 150 mg/3mL

Main information

  • Trade name:
  • Amiodarone Hydrochloride 150 mg/3mL 50 mg/mL Concentrate for injection
  • Dosage:
  • 50 mg/mL
  • Pharmaceutical form:
  • Concentrate for injection
  • Units in package:
  • Ampoule, glass, Type I, colourless, 3 mL, 10 dose units
  • Class:
  • Prescription
  • Prescription type:
  • Prescription
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug
  • Manufactured by:
  • Cambrex Profarmaco Milano Srl

Documents

Localization

  • Available in:
  • Amiodarone Hydrochloride 150 mg/3mL 50 mg/mL Concentrate for injection
    New Zealand
  • Language:
  • English

Therapeutic information

  • Therapeutic indications:
  • Treatment should be initiated only under hospital or specialist supervision. Indicated for treatment of · Tachyarrhythmias associated with Wolff-Parkinson-White Syndrome. · All types of tachyarrhythmias including · supraventricular, nodal and ventricular tachycardias, atrial flutter and fibrillation; · ventricular fibrillation; · when other agents cannot be used. The injection is to be used when a rapid response is required.

Other information

Status

  • Source:
  • Medsafe - Medicines Safety Authority - New Zealand
  • Authorization number:
  • 14561
  • Authorization date:
  • 16-07-2010
  • Last update:
  • 27-09-2017

Summary of Product characteristics: dosage,interactions,side effects

Amiodarone Hydrochloride 150 mg/3 mL

01102015

NEW ZEALAND DATA SHEET

Amiodarone Hydrochloride 150 mg/3 mL

Amiodarone hydrochloride

Concentrated Injection

150 mg/3 mL

Name of the Medicine

Non-proprietary name

Amiodarone hydrochloride

Chemical structure

CAS number

1951-25-3

Description

active

ingredient

Amiodarone

Hydrochloride

mg/3

amiodarone

hydrochloride

(2-n-butyl-3(4-(2-diethylaminoethoxy)-3,5-diiodobenzoyl)

benzofuran

hydrochloride). Amiodarone hydrochloride is a Class III antiarrhythmic agent.

Amiodarone hydrochloride is a fine white crystalline powder. It is slightly soluble in water and

is soluble in alcohol and chloroform. It is an amphiphilic compound and contains iodine in its

formulation.

The excipients of Amiodarone Hydrochloride 150 mg/3 mL are polysorbate 80, benzyl

alcohol and water for injections, as well as hydrochloric acid and sodium hydroxide for pH

adjustment.

Each 3mL ampoule contains 60.6mg of benzyl alcohol and approximately 56mg iodine.

Amiodarone Hydrochloride 150 mg/3 mL

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Pharmacology

Actions

Amiodarone is a Class III antiarrhythmic agent prolonging the action potential duration and

hence refractory period of atrial, nodal and ventricular tissues, thereby giving a very broad

spectrum of activity. An increase in the refractory period of the atrial cells is a major

contributing action to the control of atrial tachyarrhythmias.

A reduction in the permeability of the A-V node, both anterograde and retrograde, explains

the efficacy of the medicine in nodal tachycardias caused by re-entry through the A-V node.

Its action on ventricular arrhythmias is explained by a number of mechanisms. The effect on

the atrium and A-V node results in a reduction in the frequency of stimuli reaching the

ventricle thus giving the ventricular cell mass time to repolarise in cases where there has

been

desynchronisation

refractory

periods.

Furthermore,

lengthening

refractory period of the His-Purkinje system and ventricular contractile fibres reduces or

prevents micro re-entry. Amiodarone increases coronary blood flow, decreases cardiac

oxygen requirements without producing negative inotropic effects and also suppresses

ectopic

pacemakers,

this

particularly

valuable

arrhythmias

associated

with

ischaemic damage or angina pectoris.

The site and mode of action of amiodarone can be summarised in terms of its effect on

myocardial electrophysiology.

Myocardial electrophysiology

Sinus node:

It decreases sinus automaticity by reducing the slow diastolic depolarisation gradient in the

nodal

cell.

This

direct

effect

mediated

through

sympathetic

parasympathetic system.

Atrio-ventricular (A-V) node:

It reduces the speed of conduction and increases the refractory period of the A-V node.

His-Purkinje system:

It increases the refractory period but does not modify the speed of conduction of the His-

Purkinje system.

Contractile fibres:

It increases the action potential but does not alter the rate of depolarisation of the atrial or

ventricular myocardial cells; an effect that is more marked in the atria than the ventricles.

Amiodarone Hydrochloride 150 mg/3 mL

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Pharmacokinetics

The following information may not necessarily be related to i.v. administration of amiodarone,

however is included for reference purposes:

In general, pharmacokinetic data relating to amiodarone are incomplete. Amiodarone is

incompletely and erratically absorbed following oral administration. Absolute bioavailability

ranges from 22 - 86% but there is extensive inter-subject variation. First-pass metabolism in

the gut wall and/or in the liver may be a factor in determining the availability of the medicine.

A HPLC method is available for estimation of amiodarone plasma levels. However, the value

of this is limited because the correlation of therapeutic effect and plasma level has not been

established. Steady state plasma levels are generally around 1 - 2µg/mL although inter-

subject variations are common.

Considerably higher values have been reported, especially subsequent to large single doses.

Peak plasma concentrations of 6.9 ± 4.2µg/mL have been recorded following a single dose

of 1,600mg and 1.7 ± 0.3µg/mL after a single dose of 800mg. Steady state levels of 1.57 ±

0.1µg/mL and 3.9µg/mL have been recorded after daily oral dosing in the range of 800 -

1,800mg.

The half-life of amiodarone is long and with chronic oral dosing can be from 14 – 110 days

but is usually in the range 14 - 59 days. The principal metabolite of amiodarone, which has

been detected in the plasma and other tissues, is desethylamiodarone. This metabolite is

reported to have a longer half-life than amiodarone, i.e. 10 hours after a single dose of

amiodarone and 60 - 90 days after chronic dosing with amiodarone. The activity of this

metabolite is not known. Amiodarone is highly protein bound and is thought to bind strongly

to protein at concentrations of 10µg/mL. It is believed that most of the medicine is excreted

via the liver and gastrointestinal tract by biliary excretion. There may be some hepatic

recirculation.

The apparent volume of distribution after oral (200 - 400mg) amiodarone is 6.31 ± 4.93L/kg.

Amiodarone appears to accumulate in adipose tissue and in highly perfused organs (lung,

bone marrow, adrenals, liver, pancreas, heart, spleen and kidney). The concentration of

amiodarone in packed red blood cells is approximately 60% of that in plasma.

Indications

Treatment should be initiated only under hospital or specialist supervision.

Tachyarrhythmias associated with Wolff-Parkinson-White Syndrome.

All types of tachyarrhythmias including

supraventricular, nodal and ventricular tachycardias, atrial flutter and fibrillation;

ventricular fibrillation;

when other agents cannot be used.

The injection is to be used when a rapid response is required.

Amiodarone Hydrochloride 150 mg/3 mL

01102015

Contraindications

Known hypersensitivity to iodine or amiodarone or to any of the excipients.

Pregnancy and lactation (see Use in Pregnancy and Use in Lactation).

In patients in whom bradycardia or AV block is sufficient to cause syncope, patients with sick

sinus syndrome (risk of sinus arrest) or with severe atrioventricular conduction disorders,

Amiodarone

Hydrochloride

mg/3

should

only

used

conjunction

with

pacemaker.

Sinus bradycardia and sino-atrial heart block.

Amiodarone Hydrochloride 150 mg/3 mL is contraindicated in patients with evidence, or a

history of thyroid dysfunction.

Combined therapy with medicines which may induce ‘torsades de pointes’ (see Interactions).

Amiodarone Hydrochloride 150 mg/3 mL is contraindicated in the case of hypotension,

severe respiratory failure, cardiomyopathy, heart failure, circulatory collapse and severe

arterial hypotension. It is also contraindicated in bi- or trifascicular conduction disorders,

unless a permanent functioning pacemaker is fitted, or unless the patient is in a special care

unit and amiodarone is used under the cover of electrosystolic pacing.

benzyl

alcohol

content,

Amiodarone

Hydrochloride

mg/3

contraindicated in neonates (children less than one month of age) or premature neonates

(see Warnings and Precautions – Paediatric use).

Warnings and Precautions

It is recommended to perform an ECG and serum potassium measurement before treatment

initiation.

Caution

should

exercised

case

hypotension,

severe

respiratory

failure,

uncompensated or severe heart failure.

Intravenous injection is generally not advised because of haemodynamic risks (severe

hypotension, circulatory collapse); intravenous infusion is preferable whenever possible.

Intravenous injection is to be done only in emergency where alternative therapies have failed

and only in an intensive care unit under continuous monitoring (ECG, blood pressure).

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). To avoid injection

site reactions, amiodarone i.v. should, whenever possible, be administrated through a central

venous line (see Dosage and Administration). Do not mix other preparations in the same

syringe. Do not inject other preparations in the same line. If amiodarone should be continued,

this should be via intravenous infusion.

Amiodarone Hydrochloride 150 mg/3 mL

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Thyroid hormone abnormalities

As amiodarone may induce thyroid disorders, particularly in patients with personal or family

history of thyroid disorders, clinical and biological monitoring (ultrasensitive TSH (usTSH)

assay) is recommended before starting treatment, during treatment and for several months

following treatment discontinuation. Serum usTSH levels should be measured when thyroid

dysfunction

suspected.

Severe

cases,

with

clinical

presentation

thyrotoxicosis,

sometimes fatal, require emergency therapeutic management.

Amiodarone contains iodine and thus may interfere with radio-iodine uptake. However,

thyroid function tests (free-T3, free-T4, usTSH) remain interpretable. Amiodarone inhibits

peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause isolated

biochemical changes (increase in serum free-T4, free-T3 being slightly decreased or even

normal) in clinically euthyroid patients. There is no reason in such cases to discontinue

amiodarone treatment.

Hypothyroidism should be suspected if the following clinical signs, usually slight, occur:

weight gain, cold intolerance, reduced activity, excessive bradycardia. The diagnosis is

supported by a clear increase in serum usTSH. Euthyroidism is usually obtained within 1 –

3 months following the discontinuation of treatment. In life-threatening situations, amiodarone

therapy can be continued, in combination with L-thyroxine. The dose of L-thyroxine is

adjusted according to TSH levels.

Hyperthyroidism

Hyperthyroidism may occur during amiodarone treatment, or up to several months after

discontinuation. Clinical features, usually slight, such as weight loss, onset of arrhythmia,

angina, and congestive heart failure should alert the physician. The diagnosis is supported

by a clear decrease in serum ultrasensitive TSH (usTSH) level, in which case, amiodarone

should be withdrawn. Recovery usually occurs within a few months following withdrawal of

treatment; clinical recovery precedes the normalisation of thyroid function tests. Severe and

sometimes

fatal

cases,

with

clinical

presentation

thyrotoxicosis,

require

emergency

therapeutic management. The treatment should be adjusted to each individual case: for

example anti-thyroid medicines, corticosteroid therapy, beta-blockers.

Pacemakers/implantable defibrillators

In the context of chronic administration of antiarrhythmic medicines, cases of increase in

ventricular defibrillation and/or pacing threshold of pacemakers or implantable cardioverter

defibrillator devices have been reported, potentially affecting their efficacy. Therefore, a

repeated verification of the functioning of such devices before and during amiodarone

treatment is recommended.

Anaesthesia

Before surgery, the anaesthetist should be informed that the patient is taking amiodarone.

Amiodarone Hydrochloride 150 mg/3 mL

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Cardiac disorders

The pharmacological actions of amiodarone includes ECG changes such as QT prolongation

(related to prolonged repolarisation) with the possible development of U-waves. However

these changes do not reflect toxicity.

Amiodarone Hydrochloride 150 mg/3 mL is not contraindicated in patients with latent or

manifest

heart

failure

caution

should

exercised

existing

heart

failure

occasionally be worsened. In such cases amiodarone should be associated with the usual

cardiotonic and diuretic treatment.

Excessive doses may lead to atropine resistant bradycardia and to conduction disturbances,

particularly in elderly patients or during digitalis therapy. Amiodarone, like quinidine and

disopyramide, has caused atypical ventricular tachycardia. In patients with previous history of

the above condition, amiodarone should be avoided. Use of higher doses of amiodarone is

not advisable in persons with a history of atypical ventricular tachycardia previously induced

by another antiarrhythmic agent.

Treatment should be discontinued in case of onset of 2

or 3

degree AV block, sinoatrial

block, bifascicular or trifascicular block.

Onsets of new arrhythmias or worsening of treated arrhythmias, sometimes fatal, have been

reported. It is important, but difficult, to differentiate a lack of efficacy of the medicine from a

proarrhythmic effect, whether or not this is associated with a worsening of the cardiac

condition. Proarrhythmic effects are more rarely reported with amiodarone than with the other

antiarrhythmic agents, and generally occur in the context of medicine interactions and/or

electrolytic disorders (see Interactions).

Cases of severe, potentially life-threatening bradycardia and heart block have been observed

when amiodarone is used in combination with sofobuvir alone or in combination with another

hepatitis C virus (HCV) direct acting antiviral (DAA), such as daclatasvir, simeprevir or

ledipasvir.

Therefore,

co-administration

these

agents

with

amiodarone

recommended. If concomitant use with amiodarone cannot be avoided, it is recommended

that patients are closely monitored when initiating sofosbuvir alone or in combination with

other DAAs. Patients who are identified as being at high risk of bradyarrhythmia should be

continuously monitored for atleast 48 hours in an appropriate clinical setting after initiation of

concomitant

treatment

with

sofosbuvir.

long

half-life

amiodarone,

appropriate monitoring should also be carried out for patients who have discontinued

amiodarone within the past few months and are to be initiated on sofosbuvir alone or in

combination with other direct DAAs. Patients receiving these hepatitis C medicines with

amiodarone, with or without other medicines that lower heart rate, should be warned of the

symptoms of bradycardia and heart block and should be advised to seek urgent medical

advice if they experience them.

ECG monitoring

Regular ECG monitoring is recommended in patients on long-term therapy with amiodarone.

U waves, deformed T waves and QT prolongation (related to prolonged repolarisation) may

occur in the ECG because of the fixing of amiodarone in the myocardial tissues and is not an

indication for withdrawing amiodarone.

The prolongation of QT interval occurs in almost all patients as this is related to the

electrophysiological and antiarrhythmic properties of the medicine. Prolongation of the actual

Amiodarone Hydrochloride 150 mg/3 mL

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QT above 0.60 seconds rather than QTC or QRS widening, may be an important warning

sign that requires modification of therapy. Too high a dosage may lead to severe bradycardia

and to conduction disturbances with the appearance of an idioventricular rhythm (atypical

ventricular tachycardia; ‘torsades de pointes’) particularly in elderly patients or during digitalis

or other antiarrhythmic therapy. In such circumstances amiodarone should be temporarily

withdrawn.

Ocular changes

Corneal deposits develop in almost all patients and regular ophthalmological monitoring (e.g.

slit lamp biomicroscopy, visual acuity, ophthalmoscopy, etc) is recommended. If blurred or

decreased

vision

occurs,

complete

ophthalmological

examination

including

fundoscopy

should be promptly performed. Appearance of optic neuropathy and/or optic neuritis requires

amiodarone withdrawal due to the potential progression to blindness.

Pulmonary disorders

Clinical

radiological

evidence

pulmonary

fibrosis

and/or

pneumonitis

been

reported, sometimes presenting as unexplained or disproportionate dyspnoea. Regular chest

x-ray should be performed routinely in patients undergoing long-term therapy or when

diagnosis is suspected. The effect has usually been reversible with corticosteroid therapy

and/or reduction or withdrawal of amiodarone therapy.

Onset of dyspnoea or non-productive cough may be related to pulmonary toxicity (see

Adverse Effects) such as interstitial pneumonitis. Very rare cases of interstitial pneumonitis

have been reported with intravenous amiodarone. A chest x-ray should be performed when

the diagnosis is suspected, in patients developing effort dyspnoea whether isolated, or,

associated

with

deterioration

general

health

status

(fatigue,

weight

loss,

fever).

Amiodarone

therapy

should

re-evaluated

since

interstitial

pneumonitis

generally

reversible following early withdrawal of amiodarone (clinical signs usually resolving within 3 -

4 weeks, followed by slower radiological and lung pulmonary function improvement within

several months), and corticosteroid therapy should be considered.

Very rare cases of severe respiratory complications, sometimes fatal, have been observed

usually

period

immediately

following

surgery

(adult

acute

respiratory

distress

syndrome); a possible interaction with a high oxygen concentration may be implicated.

Hepatic dysfunction

Regular monitoring of liver function tests (transaminases) is recommended as soon as

amiodarone is started and during treatment.

Elevation of liver enzyme levels (e.g. serum aspartate aminotransferase, serum alanine

aminotransferase, glutamyl transpeptidase) occurs quite commonly in patients undergoing

treatment with amiodarone and in some cases are asymptomatic. The changes appear to be

dose dependent rather than an idiosyncratic type. Hepatotoxicity has occasionally been

reported (see Adverse Effects) and close monitoring of hepatic function with liver function

tests is recommended as soon as amiodarone is started, and regularly during treatment.

Acute

liver

disorders

(including

severe

hepatocellular

insufficiency

hepatic

failure,

sometimes fatal) and chronic liver disorders may occur with oral and intravenous forms and

within the first 24 hours of i.v. amiodarone. Therefore, amiodarone dose should be reduced

Amiodarone Hydrochloride 150 mg/3 mL

01102015

or the treatment discontinued if the transaminases increase exceeds three times the normal

range.

Use in hepatic disease

Because of the potential risk of hepatotoxicity and/or accumulation, amiodarone should be

used with extreme caution in patients with hepatic disease.

Skin reaction

Photosensitivity is quite common and there is a wide spectrum of skin reactions, ranging

from an increased propensity to suntan to intense burning and erythema and swelling of the

exposed area. The intensity of these reactions could be alleviated by a reduction in dosage

or by application of a protective sunscreen. Patients should be instructed to avoid exposure

to the sun or use protective measures during therapy.

Some patients have developed skin pigmentation (slate grey/purple colour) of the exposed

areas. This pigmentation can be avoided if doses are kept as low as possible. If the

pigmentation is cosmetically unsightly, amiodarone should be discontinued if alternative

therapy is possible.

If symptoms or signs of Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis

(TEN) (e.g. progressive skin rash often with blisters or mucosal lesions) are present,

amiodarone treatment should be discontinued immediately.

Neurological toxicity

Peripheral neuropathy could occur in patients on long-term high dosage (generally over

400mg/day) regime.

Intracellular inclusion bodies, similar to those seen in skin, have been demonstrated in

peripheral nerve fibres. Sensorimotor neuropathy, with a glove and stocking distribution, and

myopathy have been reported in patients. Histologically, segmental demyelination of the

nerve

fibres

also

been

demonstrated.

After

discontinuation

medicine,

neurological complication is slowly and incompletely resolved.

Use in renal disease

Renal excretion of the medicine is minimal. This suggests that modification of the dose of

amiodarone in patients with renal failure is unnecessary.

Hypotension

Hypotension may occur when amiodarone hydrochloride concentrated injection is given by

the intravenous route. In some cases, hypotension may be refractory, resulting in fatal

outcomes (see Adverse Effects - Amiodarone hydrochloride concentrated injection).

Amiodarone Hydrochloride 150 mg/3 mL

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Drug interactions

Concomitant

amiodarone

recommended

with

following

medicines:

beta-blockers,

heart

rate

lowering

calcium

channel

inhibitors

(verapamil,

diltiazem)

stimulating laxative agents which may cause hypokalaemia (see Interactions).

Use in pregnancy

Category C

Amiodarone is contraindicated in pregnancy.

No teratogenic effects have been observed in animals. The medicine does cross the

placenta.

Because of the long half-life of amiodarone and its major metabolite, and the potential to

cause abnormal thyroid function, the effects on the foetal thyroid gland and bradycardia in

the foetus, its use is probably best avoided in the three months before and throughout the

duration of pregnancy. Where exposure of the foetus is unavoidable, thyroid function

(including TSH) should be assessed promptly in the newborn infant.

Amiodarone Hydrochloride 150 mg/3 mL contains benzyl alcohol (see Description). The

administration of medicines containing benzyl alcohol to neonates or premature neonates

has been associated with fatal “gasping syndrome”. As benzyl alcohol may cross the

placenta, Amiodarone Hydrochloride 150 mg/3 mL should be used with caution in pregnancy.

The following information may not necessarily be related to i.v. administration of amiodarone,

however is included for reference purposes:

In one study a 35 year old woman administered amiodarone in the last weeks of pregnancy,

transplacental passage of amiodarone and desethylamiodarone was found to be 10% and

25%, respectively. Changes in maternal thyroid function were similar to those seen in other

patients receiving amiodarone therapy, but there was no evidence of clinical hyperthyroidism.

The baby's TSH level on day 4 was normal, it had no goitre and was clinically euthyroid.

However, the authors caution the use of amiodarone in pregnancy or in those likely to

conceive whilst on amiodarone therapy. The long half-life of the medicine requires that the

medicine be stopped several months before conception. The possible adverse effects of

amiodarone on the foetal thyroid are of concern since administration of iodine (of which there

are 75mg in a 200mg dose of amiodarone) during pregnancy may cause foetal goitre,

hypothyroidism and mental retardation.

Another patient received 800mg amiodarone for 1 week (maintenance dose thereafter was

400mg daily) in her 34

week of pregnancy. Neonatal levels of amiodarone were 25% of the

maternal level. Although the infant's liver and thyroid function tests were normal, it was

bradycardic during labour and for the first 48 hours after birth.

Use in lactation

Amiodarone is contraindicated in breast-feeding mothers. As amiodarone and its desethyl

metabolite

secreted

breast

milk,

safety

newborn

been

established,

should

given

nursing

mothers.

situation

demands

that

amiodarone be given to a nursing mother, alternative infant feeding should be instituted.

Amiodarone Hydrochloride 150 mg/3 mL

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Effects on ability to drive and use machines

According to the safety data for amiodarone, there is no evidence that amiodarone impairs

the ability to drive a vehicle or operate machinery

.

Paediatric use

The safety and efficacy of amiodarone in paediatric patients have not been established.

Therefore its use in paediatric patients is not recommended.

Amiodarone Hydrochloride 150 mg/3 mL contains benzyl alcohol (see Description). There

have been reports of fatal "gasping syndrome" in neonates (children less than one month of

age) or premature neonates following the administration of intravenous solutions containing

this preservative. Symptoms include a striking onset of gasping syndrome, hypotension,

bradycardia, and cardiovascular collapse. Amiodarone Hydrochloride 150 mg/3 mL should

not be given to neonates or premature neonates.

Use in the elderly

In the elderly, heart rate may decrease markedly.

Carcinogenicity

In a carcinogenicity study in rats, amiodarone caused a dose-related increase in thyroid

follicular tumours (adenomas and/or carcinomas) in both sexes. Although mutagenicity

findings were negative, an epigenic rather than genotoxic mechanism is proposed for this

type of tumour induction. In the mouse, carcinomas were not observed but dose dependent

thyroid follicular hyperplasia was seen. The relevance of these findings to man is unknown.

Clinical experience has indicated that amiodarone can affect thyroid function.

Interactions

Pharmacodynamic Interactions

Medicines inducing ‘torsades de pointes’

Combined therapy with medicines that may induce 'torsades de pointes' is contraindicated

(see Contraindications):

Antiarrhythmic agents such as:

Class IA antiarrhythmic agents, including:

Disopyramide - combined treatment of amiodarone and disopyramide causes an

increase in the QT interval.

Procainamide

-

serum

level

procainamide

increases

significantly

with

administration

amiodarone

secondary

this

increase

cardiac,

gastrointestinal and neural toxicity may develop.

Amiodarone Hydrochloride 150 mg/3 mL

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Quinidine - atypical ventricular tachycardia with QT prolongation may develop after

amiodarone is added to a stable quinidine regimen. This is thought to be due to

either a change in the protein or receptor binding of quinidine. Serum levels of

quinidine can increase significantly with concomitant amiodarone therapy. Careful

monitoring of the electrocardiogram for QT interval prolongation and of serum levels

of quinidine is indicated when amiodarone is added to quinidine treatment.

Mexiletine - co-administration with amiodarone increases the QT interval.

Sotalol

Bepridil

Non-antiarrhythmic agents such as:

Vincamine, some neuroleptic agents, cisapride, erythromycin i.v. or pentamidine i.v., as there

is an increased risk of potentially lethal 'torsades de pointes'.

Medicines prolonging QT

Co-administration of amiodarone 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 ‘torsades de pointes’ may increase (see Warnings and Precautions) and patients

should be monitored for QT prolongation.

Fluoroquinolones should be avoided in patients receiving amiodarone.

Medicines lowering heart rate or causing automaticity or conduction disorders

Combined therapy with the following medicines is not recommended:

Beta adrenergic blocking medicines - amiodarone itself exhibits non-competitive alpha

and beta adrenergic inhibition. It should be used with caution in patients on beta blockers as

it may potentiate bradycardia and conduction disorders may occur.

Calcium antagonists - co-administration of amiodarone with medicines of the calcium

antagonist type may lead to undue bradycardia and conduction disorders may occur.

MAO inhibitors - co-administration with monoamine oxidase inhibitors is contraindicated on

theoretical grounds.

Medicines which may induce hypokalaemia

Combined therapy with the following medicines is not recommended:

Stimulant laxative agents - their use may cause hypokalaemia and therefore increase the

risk of 'torsades de pointes’; other types of laxative agents should be used.

Caution should be exercised when using the following medicines in combination with

Amiodarone Hydrochloride 150 mg/3 mL:

Diuretics inducing hypokalaemia, either alone or combined

Systemic corticosteroids (gluco-, mineralo-); tetracosactrin

Amphotericin B (i.v.).

Amiodarone Hydrochloride 150 mg/3 mL

01102015

It is necessary to prevent the onset of hypokalaemia (and to correct hypokalaemia); the QT

interval should be monitored and, in case of 'torsades de pointes', antiarrhythmic agents

should not be given (ventricular pacing should be initiated; i.v. magnesium may be used).

General anaesthesia (see Warnings and Precautions and Adverse Effects)

Potentially

severe

complications

have

been

reported

patients

undergoing

general

anaesthesia, such as bradycardia unresponsive to atropine, hypotension, disturbances of

conduction, decreased cardiac output.

A few cases of severe respiratory complications, such as adult acute respiratory distress

syndrome, sometimes fatal, have been observed most often in the period immediately after

surgery. A possible interaction with a high oxygen concentration may be implicated.

Effect of amiodarone on other medicines

Amiodarone and/or its metabolite, desethylamiodarone, inhibit CYP 1A1, CYP 1A2, CYP

3A4, CYP 2C9, CYP 2D6 and P-glycoprotein and may increase exposure of their substrates.

Due to the long half-life of amiodarone, interactions may be observed for several months

after discontinuation of amiodarone.

P-gp substrates

Amiodarone is a P-gp inhibitor. Co-administration with P-gp substrates is expected to result

in an increase of their exposure.

Digitalis

-

digoxin

co-administration

amiodarone

patients

already

receiving

digitalis increases plasma digoxin concentrations by about 70%. This is possibly due to

the decrease in digoxin clearance, and therefore precipitates toxicity and could lead to

disturbances in automaticity (severe bradycardia) and conduction disturbances with the

appearance

idioventricular

rhythm.

mechanism

action

unknown

amiodarone may displace tissue glycoside or interfere with digoxin excretion. ECG and

digoxin plasma levels should be monitored and patients should be observed for clinical

signs of digoxin toxicity. It may be necessary to adjust dosage of digoxin treatment.

Dabigatran - caution should be exercised when amiodarone is co-administered with

dabigatran due to the risk of bleeding. It may be necessary to adjust the dosage of

dabigatran as per its label.

CYP 2C9 substrates

Amiodarone raises the concentrations of CYP 2C9 substrates such as warfarin or phenytoin

by inhibition of the cytochrome P450 2C9.

Warfarin and other anticoagulant agents - amiodarone raises the concentration of

warfarin. The combination of warfarin with amiodarone potentiates the effect of the

anticoagulant therapy and increases the risk of bleeding. More frequent monitoring of

prothrombin (INR) level and dosage adjustment of oral anticoagulant during treatment

with and after discontinuation of amiodarone therapy is necessary.

Phenytoin - amiodarone raises plasma concentrations of phenytoin. The combination

of phenytoin and amiodarone may lead to increases in plasma phenytoin levels with

signs of overdosage (particularly neurological signs); clinical monitoring should be

Amiodarone Hydrochloride 150 mg/3 mL

01102015

undertaken and phenytoin dosage should be reduced as soon as overdosage signs

appear; phenytoin plasma levels should be determined.

CYP 2D6 substrates

Flecainide - amiodarone increases the concentration of flecainide plasma levels. The

dosage of flecainide should be adjusted.

CYP 3A4 substrates

When such medicines are co-administered with amiodarone, an inhibitor of CYP 3A4, this

may result in a higher level of their plasma concentrations, which may lead to a possible

increase in their toxicity.

Cyclosporin - dosage should be adjusted.

Fentanyl - combination with amiodarone may enhance the pharmacologic effects of

fentanyl and increase the risk of its toxicity.

Statins metabolised by CYP 3A4 - the risk of muscular toxicity is increased by

concomitant administration of amiodarone with statins metabolised by CYP 3A4 such

as simvastatin, atorvastatin and lovastatin. It is recommended to use a statin not

metabolised by CYP 3A4 when given with amiodarone.

Other - lignocaine, tacrolimus, sildenafil, midazolam, triazolam, dihydroergotamine,

ergotamine, colchicine.

Effect of other medicines on amiodarone

CYP 3A4 inhibitors and CYP 2C8 inhibitors may have a potential to inhibit amiodarone

metabolism and to increase its exposure. It is recommended to avoid CYP 3A4 inhibitors

(e.g. grapefruit juice and certain medicines) during treatment with amiodarone.

Co-administration of amiodarone with sofosbuvir alone or in combination with another HCV

direct acting antiviral (such as daclatasvir, simeprevir or ledipasvir), is not recommended as it

may lead to serious symptomatic bradycardia. The mechanism for this bradycardia effect is

unknown. If co-administration cannot be avoided, cardiac monitoring is recommended (see

Warning and Precautions)."

Other consideration should be given to the possibility that amiodarone may alter the plasma

concentration of other medicines, particularly those which are highly protein bound.

Effect on laboratory tests

Thyroid function tests

Amiodarone contains 2 atoms of iodine and bears a structural resemblance to the molecule

of thyroxine. A 300mg maintenance dose of amiodarone has been reported to yield 9mg/day

of iodine at steady state, well in excess of the highest normal dietary intake.

Amiodarone Hydrochloride 150 mg/3 mL

01102015

As a consequence of taking the medicine and in the absence of any clinical thyroid

dysfunction, changes in tests of thyroid function may occur, variable in number and degree.

Typically, the PBI, iodine uptake, serum thyroxine (T4), reverse triiodothyronine (rT3) and

free thyroxine index (FTI) rise, and serum triiodothyronine (T3) falls.

Abnormalities, either multiple or single, may occur in approximately 12% of patients. In

particular, a low T3 syndrome has been described, as with other medicines such as

dexamethasone.

General

It has been shown that there is a physical incompatibility of heparin and aminophylline with

amiodarone

when

mixed

infusion

administration

set.

recommended

that

amiodarone for infusion not be mixed with other medicines.

Adverse Effects

Amiodarone has been reported to cause frequent and potentially serious toxicity. The

incidence, variety and severity of the effects varies from study to study. Most of the adverse

effects are also related to dosage and duration of amiodarone, concurrent use of other

antiarrhythmic

agents,

severity

underlying

disease

state,

individual

variation

pharmacokinetic profile of the medicine.

Amiodarone hydrochloride concentrated injection

Amiodarone

hydrochloride

concentrated

injection

cause

moderate

transient

reduction in blood pressure, and circulatory collapse may be precipitated by too rapid

administration

overdosage.

Atropine

been

successfully

used

such

patients

presenting with bradycardia. Temporary hot flushes, sweating, and nausea have also been

reported with amiodarone hydrochloride concentrated injection.

Local

Possible inflammation of veins following intravenous infusion that may be avoided by the use

of a central venous catheter. Common injection site reactions such as pain, erythema,

urticaria,

oedema,

necrosis,

extravasation,

infiltration,

inflammation,

induration,

thrombophlebitis, phlebitis, cellulitis, infection, pigmentation changes.

Systemic

Hot flushes and sweating have been reported rarely.

Common reports of decrease in blood pressure, usually moderate and transient have been

received. Cases of severe hypotension or collapse have been reported following overdosage

or a too rapid injection.

Cases of neutropenia and agranulocytosis have been reported.

Amiodarone Hydrochloride 150 mg/3 mL

01102015

Moderate

bradycardia

some

cases,

especially

patients

with

sinus

node

dysfunction and/or elderly patients, marked bradycardia, or more exceptionally sinus arrest,

requires the discontinuation of therapy.

Occurrence of arrhythmia, or aggravation of the pre-existing trouble, followed in some cases

by cardiac arrest, have been reported. In view of current knowledge, it is not possible to

differentiate what may be due to the medicine from what may be related to the underlying

cardiac condition, or what may be the result of a lack of efficacy of therapy. These effects are

more rarely reported than with most of the other antiarrhythmic agents, and they occur in

general in case of certain medicine interactions or electrolyte disorders.

Cases of torsades de pointes have been reported.

Isolated elevation of serum transaminases, which are usually moderate (1.5 - 3 times

normal) have been reported at the beginning of therapy. They may regress with dose

reduction or even spontaneously.

Cases of hyperthyroidism and syndrome of inappropriate antidiuretic hormone secretion

(SIADH) have been reported.

Very rare cases of acute liver disorders with elevated serum transaminases and/or jaundice,

which included hepatic failure, some fatal, have also been reported. Treatment should be

discontinued and monitoring of liver function tests is therefore recommended.

Cases of pancreatitis/acute pancreatitis have been reported.

Very rare cases of interstitial pneumonitis have been reported with intravenous amiodarone.

When the diagnosis is suspected, chest x-ray should be performed. Amiodarone therapy

should be re-evaluated since interstitial pneumonitis is generally reversible following early

withdrawal of amiodarone, and corticosteroid therapy should be considered.

Very rare cases of severe respiratory complications, sometimes resulting in death, have

been observed usually in the period immediately following surgery (acute adult respiratory

distress syndrome), sometimes fatal: a possible interaction with high oxygen concentrations

implicated.

Bronchospasm

and/or

apnoea

case

pre-existing

severe

respiratory failure and especially in asthmatic patients have also been reported.

isolated

cases

anaphylactic

shock

benign

intra-cranial

hypertension

(pseudotumor cerebri) have been reported.

Nausea and headache have been reported very rarely. Cases of confusional state, delirium,

hallucinations and libido decrease have been reported. Isolated cases of angioneurotic

oedema (Quincke's oedema) have been reported.

Cases of eczema, urticaria, severe skin reactions sometimes fatal, including Toxic Epidermal

Necrolysis/Stevens-Johnson

Syndrome,

bullous

dermatitis

medicine

reaction

with

eosinophilia and systemic symptoms have been reported.

Back pain.

Amiodarone Hydrochloride 150 mg/3 mL

01102015

Dosage and Administration

Amiodarone Hydrochloride 150 mg/3 mL should only be used when facilities exist for cardiac

monitoring and defibrillation, should the need arise. Intravenous injection is generally not

advised

because

haemodynamic

risks

(severe

hypotension,

circulatory

collapse).

Intravenous infusion should be preferred whenever it is possible.

Infusion

The standard recommended dose is 5mg/kg body weight given by intravenous infusion over

a period of 20 minutes to 2 hours. This should be administered as a dilute solution in 250mL

5% glucose. AMIODARONE HYDROCHLORIDE 150 MG/3 ML IS INCOMPATIBLE WITH

SALINE AND SHOULD BE ADMINISTERED SOLELY IN 5% GLUCOSE SOLUTION.

This may be followed by repeat infusions up to a maximum of 1,200mg/day (approximately

15mg/kg body weight) in up to 500mL 5% glucose per 24 hours, the rate of infusion being

adjusted on the basis of clinical response.

When given by infusion, Amiodarone Hydrochloride 150 mg/3 mL may reduce drop size and,

if appropriate, adjustments should be made to the rate of infusion.

Repeated or continuous infusion via the peripheral veins may lead to local discomfort and

inflammation. When repeated or continuous infusion is anticipated, administration by a

central venous catheter is recommended.

Injection

extreme

clinical

emergency

Amiodarone

Hydrochloride

mg/3

may,

discretion of the clinician, be given as a slow injection of 150 - 300mg in 10 - 20mL

5% glucose

over

minimum

minutes.

This

should

repeated

least

15 minutes. Patients treated in this way must be closely monitored, e.g. in an intensive care

unit.

Changeover from i.v. to oral therapy

Oral therapy should be initiated concomitantly at the usual loading dose i.e. 200mg 3 times a

day as soon as possible after an adequate response has been obtained using Amiodarone

Hydrochloride 150 mg/3 mL, which should then be phased out gradually, and an overlap of

oral and intravenous medication of up to two days is recommended to prevent plasma levels

falling and efficacy being lost.

Instructions for Handling

The dilution is to be made under aseptic conditions. The solution is to be inspected visually

for particulate matter and discoloration prior to administration. The solution should only be

used if the solution is clear and free from particles.

Experience has shown that amiodarone can be absorbed into PVC infusion bags and

administration sets possibly because of the presence of plasticisers in PVC plastic. It is

important to prepare the infusion solution immediately prior to use in either glass or rigid PVC

bottles containing no plasticisers.

Amiodarone Hydrochloride 150 mg/3 mL

01102015

The use of medical equipment or devices containing plasticiser such as DEHP (di-2-

ethylhexyl phthalate) in the presence of amiodarone injection may result in leaching out of

DEHP. In order to minimise patient exposure to DEHP, the final amiodarone dilution for

infusion should preferably be administered through non-DEHP containing sets.

Incompatibilities

Amiodarone

Hydrochloride

mg/3

incompatible

with

saline

should

administered solely in 5% glucose solution.

Do not mix amiodarone with other preparations in the same syringe or infusion solution.

Solutions containing less than 2 ampoules Amiodarone Hydrochloride 150 mg/3 mL in

500mL 5% glucose are unstable and should not be used.

Use in the elderly

As with all patients it is important 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 used. Particular

attention should be paid to monitoring of thyroid function.

Overdose

Overdosage may lead to severe bradycardia and to conduction disturbances with the

appearance of an idioventricular rhythm, particularly in elderly patients or during digitalis

therapy.

these

circumstances

amiodarone

should

temporarily

withdrawn

necessary beta adrenostimulants or glucagon given. In the event of ingestion of a toxic dose,

gastric lavage should be employed to reduce absorption and in addition general supportive

measures should be applied.

The following information may not necessarily be related to i.v. administration of amiodarone,

however is included for reference purposes:

A case of attempted suicide with 2,600mg amiodarone is reported in the literature. No clinical

symptoms, changes in heart rate or blood pressure were reported. The ECG revealed

considerable lengthening of the QT interval and T wave inversion in the precordial leads with

transient disappearance of R wave in leads V1 to V4, simulating an antero-septal infarction.

In another case of attempted suicide with 8 g amiodarone, the only symptoms reported were

profuse perspiration. No signs of cyanosis, dyspnoea or decreased sensitivity were found.

No clinical side effects were documented over the monitored period of 3 months.

Amiodarone Hydrochloride 150 mg/3 mL

01102015

Presentation and Storage Conditions

Amiodarone Hydrochloride 150 mg/3 mL is a clear, pale yellow solution for intravenous

administration.

Each 3mL ampoule contains 150mg amiodarone hydrochloride. The ampoules are packed in

units of 10 on a tray contained in a cardboard carton.

Shelf-Life

Packaged for sale: 2 years

Following dilution: After dilution in 5% glucose, chemical and physical in-use stability has

been demonstrated for 36 hours at 25°C when exposed to light.

From a microbiological point of view, the diluted solution should be used immediately. If not

used immediately, in-use storage times and conditions prior to use are the responsibility of

the user and would normally not be longer than 24 hours at 2°C - 8°C unless dilution has

taken place in controlled and validated aseptic conditions.

For single use only. Discard any unused solution.

Special Precautions for Storage

Store at 2°C to 8°C (refrigerate, do not freeze). Protect from light.

Sponsor Details

BNM Group

39 Anzac Road

Browns Bay

Auckland 0753

Ph: 0800 565 633

Medicine Schedule

Prescription Medicine

Date of Preparation

01 October 2015

28-11-2018

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21-5-2018

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21-5-2018

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15-5-2018

Votrient (Novartis Europharm Limited)

Votrient (Novartis Europharm Limited)

Votrient (Active substance: Pazopanib hydrochloride) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)3062 of Tue, 15 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/1141/T/46

Europe -DG Health and Food Safety

21-3-2018

EU/3/11/919 (Monopar Therapeutics SARL)

EU/3/11/919 (Monopar Therapeutics SARL)

EU/3/11/919 (Active substance: Clonidine hydrochloride) - Transfer of orphan designation - Commission Decision (2018)1817 of Wed, 21 Mar 2018 European Medicines Agency (EMA) procedure number: EMA/OD/069/11/T/02

Europe -DG Health and Food Safety