INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo HEXARONE 100 (tablets)
HEXARONE 200 (tablets)

HAPP102

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

HEXARONE 100 (tablets)
HEXARONE 200 (tablets)

COMPOSITION
Each Hexarone 100 tablet contains 100 mg
amiodarone hydrochloride.
Each Hexarone 200 tablet contains 200 mg amiodarone hydrochloride.

PHARMACOLOGICAL CLASSIFICATION
A.6.2. Cardiac suppressants

PHARMACOLOGICAL ACTION
Amiodarone is predominantly a Class III antiarrhythmic agent.
Amiodarone prolongs the duration of the action potential, particularly in the nodal and Purkinje tissue.
Amiodarone does not seem to alter the resting membrane potential, but depresses membrane responsiveness and prolongs the refractory period in the atria, AV node, His-Purkinje system, ventricles and accessory atrioventricular pathways.
The conduction rate is reduced in the atria, AV node and accessory pathways.
Amiodarone also exhibits non competitive alpha and beta adrenoreceptor antagonism.
Amiodarone is strongly protein bound and the plasma half life is usually approximately 50 days. There may, however, be considerable inter-patient variation.

INDICATIONS
Prevention of tachyarrhythmias associated with Wolff-Parkinson-White syndrome and other types of tachyarrhythmias of paroxysmal nature, including supraventricular, nodal and ventricular tachycardias, atrial flutter and atrial fibrillation and ventricular fibrillation, when other medicines cannot be used.

CONTRA-INDICATIONS
Amiodarone is contra-indicated in patients with sinus bradycardia and sino-atrial heart block.
Amiodarone should be used only in conjunction with a pace-maker when treating patients with severe conduction disturbances (e.g. high grade AV block, bifascicular or trifascicular block)
Amiodarone is contra-indicated in patients with evidence or history of thyroid dysfunction.
Since Amiodarone contains iodine, it should be avoided in patients with a known sensitivity to iodine.
Contra-indicated in patients with severe respiratory failure.
Amiodarone may induce erratic results from thyroid function tests (see side effects and special precautions)
Too high a dosage may lead to severe bradycardia and to conduction disturbances with the appearance of idioventricular rhythm, particularly in elderly patients or during digitalis therapy. In these circumstances therapy should be withdrawn. If necessary, beta adrenostimulants or glucagon may be given.
Amiodarone is not contra-indicated in patients with latent or manifest heart failure, but caution should be exercised as existing heart failure may be worsened by amiodarone.
Amiodarone is contra-indicated during pregnancy and lactation.

WARNINGS
Patients being treated with amiodarone should avoid excessive exposure to sunlight.
Avoid the use of amiodarone in patients suffering from porphyria.

DOSAGE AND DIRECTIONS FOR USE
The minimum effective dose should be used at all times. Dosage should be adjusted according to individual patient’s response and well being.
The following dosage regimen is generally effective.
Initial stabilization - initiate treatment with 200 mg three times daily for one week. Reduce this dosage to 200 mg twice daily for a further week.
Maintenance - following the initial stabilization period, the dosage should be reduced to 200 mg daily, or less, if appropriate.
The scored 100 mg tablet should be used to titrate the minimum dosage. The maintenance dose should be regularly reviewed, especially where this exceeds 200 mg daily.
GENERAL CONSIDERATIONS:
It is necessary to administer high initial doses because the onset of action is slow, whilst the necessary tissue levels of amiodarone are being achieved.
Amiodarone has a very low acute toxicity , therefore few serious problems have been observed during this initial phase.
Excessive dosing during maintenance therapy may cause side effects which are thought to be due to excessive tissue retention of amiodarone and / or its metabolites.
The side effects gradually disappear as the tissue levels of amiodarone decline following reduction of dosage or withdrawal of amiodarone.
Once amiodarone treatment is withdrawn, residual tissue bound amiodarone may protect the patient for up to one month, but the likelihood of the reoccurrence of cardiac arrhythmias, during this period should be considered.
Patients should be regularly monitored for clinical signs of overdosage and the dosage should be adjusted accordingly.
It is most important that the minimum effective dose be used.
Use in the elderly:
It is important that the minimum effective dose be used.
Whilst there is no evidence that dosage requirements are different in the elderly, they may be more susceptible to bradycardia and conduction defects if too high a dose is administered. Particular attention should be paid to monitoring thyroid function.
See contra-indications, Precautions, Warnings and Side-effects.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Since the occurrence of certain side effects may be evident only after prolonged use, patients should be continually monitored.
Opthalmological: Following continuous therapy, some patients may develop micro-deposits in the cornea.
The deposits are usually only visible by slit light examination and very rarely give rise to symptoms such as visual haloes.
These microdeposits regress on reduction or discontinuation of amiodarone and are considered benign in nature.
Impaired visual acuity due to optic neuritis has been observed.
Regular opthalmological examinations are recommended during long term therapy.
Cardiac: Bradycardia which is generally moderate and dose dependant has been reported. In some cases (sinus node disease, elderly patients) marked bradycardia or sinus arrest has occurred. Rare instances of conduction disturbances (sino-atrial block, various degrees of AV block) have been reported.
The proarrhythmic effect of amiodarone has usually occurred in combination with other precipitating factors, particularly other antiarrhythmic agents, digoxin and hypokalaemia
Dermatological: Photosensitisation may be induced in certain individuals - this can usually be alleviated by the use of total sun block barrier creams and other protective measures.
Less frequently a bluish discolouration of the skin has been reported. This pigmentation is usually slowly reversible on discontinuation of amiodarone, but may not completely disappear.
Thyroid: Both hyper- and hypothyroidism have been reported either during or soon after treatment with amiodarone.
Monitoring of the usual thyroid tests may be confusing because some (PBI and 131I uptake) are invalidated and others (T4, T3 and FTI), may be altered, where the patient is clearly euthyroid. Clinical monitoring is therefore recommended and should be continued for several months following discontinuation of amiodarone therapy.
This follow up monitoring is particularly important in the elderly. In patients who have a history of thyroid dysfunction, regular testing is recommended.
Clinical features of hyperthyroidism, such as mass loss, asthenia, restlessness, increase in heart rate or the recurrence of cardiac dysrhythmia, angina or congestive heart failure, should alert the clinician.
The diagnosis may be supported by an elevated serum tri-iodothyronine (T3), a low level of thyroid stimulating hormone (TSH) and a reduced TSH response to thyrotropin releasing hormone (TRH). Elevation of reverse T3 (rT3) may also be found.
Clinical features of hypothyroidism such as mass 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 may be low.
In the case of hyperthyroidism amiodarone should be withdrawn.
In cases of severe hyperthyroidism, courses of antithyroid medication have been used and large doses are required initially. These may not always be effective and concomitant high dose corticosteroids may be required for several weeks. Thyroid hypofunction usually resolves within 3 months of discontinuation of amiodarone therapy and it may be treated cautiously with L-thyroxine.
Concomitant use of amiodarone is only advocated in life threatening situations, when TSH levels may provide a guide to the dosage of L-thyroxine.
Pulmonary: Severe pulmonary toxicity has been reported, including fibrosis and interstitial pneumonitis. Diffuse pulmonary alveolitis may also occur, sometimes presenting as unexplained or disproportionate dyspnoea.
There may be an associated deterioration in general health (mass loss, fever, fatigue). Patients developing dyspnoea, without signs of cardiac failure or loss of control of arrhythmias, should be clinically evaluated, including lung function tests and chest X-ray.
Pulmonary alveolitis is usually reversible on early discontinuation of amiodarone use, with or without concomitant use of corticosteroids. Clinical symptoms often resolve within weeks followed by slower radiological and lung function improvement.
These pulmonary effects may be potentially fatal.
Hepatic: Liver function, particularly transaminases, should be monitored before treatment and periodically thereafter. At the beginning of therapy elevation of serum transaminases which can be in isolation (1,5 to 3 times normal) may occur. These may return to normal with dose reduction or sometimes spontaneously. Occasional cases of acute liver disorders with elevated serum transaminases and / or jaundice may occur. These normally resolve once treatment has been withdrawn.
There have been reports of chronic liver disease during long term therapy. Alteration of laboratory tests (transaminases elevated 1,5 to 3 times) or clinical signs (possible hepatomegaly), during treatment of longer than 6 months, should suggest this diagnosis. Routine monitoring of liver function tests is advised. A few cases of irreversible progression have been reported. Histological findings may resemble pseudo-alcoholic hepatitis - they can be variable and may include cirrhosis.
Neurological: Peripheral neuropathy and or myopathy. These conditions may be serious and may be reversible on withdrawal of amiodarone.
Nightmares, vertigo, headaches and sleeplessness may occur. Tremor and ataxia have also been reported, usually with complete regression following reduction of dose or withdrawal of treatment. Benign raised intra-cranial pressure has been reported.
ECG: Amiodarone will induce ECG changes : QT interval lengthening corresponding to prolonged repolarisation, U waves and deformed T waves may occur because of the fixing of amiodarone in the cardiac tissue. These are not signs of toxicity and dosing may continue.
Other: Nausea, vomiting, metallic taste (which usually occur with loading dose and which regress on dose reduction) fatigue and epididymo-orchitis have been reported. Isolated cases suggesting hypersensitivity have been reported. Symptoms include vasculitis, renal involvement with moderate elevation of creatinine levels or thrombocytopaenia have been observed.

INTERACTIONS
Digoxin
: Co-administration of digoxin and amiodarone may cause a rise in the plasma digoxin levels. The patient should be monitored and the digoxin dose should be adjusted as necessary. A synergistic effect on heart rate and atrioventricular conduction is possible.
Anticoagulant therapy: Amiodarone may cause raised plasma levels of the anticoagulants and thus their activity may be potentiated. More frequent monitoring of prothrombin time during treatment and after discontinuation of therapy with amiodarone is recommended.
Highly protein bound medicines: Amiodarone may alter the concentrations of these medicines e.g. phenytoin.
Beta blockers and certain calcium channel blockers (verapamil and diltiazem): Potentiation of negative chronotropic and dromotropic properties may occur. This combination should be strictly monitored.
Medicines which prolong the QT interval - e.g. quinidine and disopyramide may lead to an increased risk of Torsades des Pointes.
Medicines which induce hypokalaemia - e.g. diuretics, may also lead to an increased risk of Torsades des Pointes.
The use of amiodarone with other antiarrhythmics (particularly Class I) needs particularly careful consideration.
Sotalol: Combination with amiodarone is contra-indicated, because of the effects on repolarisation.
General anaesthesia: Potentially severe complications have been reported in patients taking amiodarone ; bradycardia unresponsive to atropine, hypotension, disturbances of conduction, decreased cardiac output. A few cases of acute respiratory distress, in the period immediately after cardiovascular surgery have been observed. Possible increase of the toxic effect of oxygen has been implicated.
The anaesthetist should always be informed that the patient is taking amiodarone.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
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. In these circumstances amiodarone therapy should be withdrawn. Gastric lavage may be employed to reduce absorption, in addition to general supportive measures. Patients 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 amiodarone adequate and prolonged surveillance of the patient, particularly cardiac status, is recommended.

IDENTIFICATION
Hexarone 100 tablets:
White, round tablets, biconvex with a one sided score notch. Diameter : 8,0-8,2 mm, Height 3,2 - 3,5 mm
Hexarone 200 tablets: White, round tablets, biconvex with a one sided score notch. Diameter : 10,0-10,2 mm, Height 4,0 - 4,2 mm

PRESENTATION
White, opaque PP/Aluminium blisters. Packs of 30’s.

STORAGE INSTRUCTIONS
Store in a well closed container below 25°C, protected from light.
KEEP OUT OF REACH OF CHILDREN.
Do not remove blisters/tablets from outer container until required for use.

REGISTRATION NUMBER
Hexarone 100 tablets
: 32/6.2/0650
Hexarone 200 tablets: 32/6.2/0651

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Hexal Pharma (SA) (PTY) Ltd
46 Mahogany Road
Mahogany Ridge
Westmead
3608

DATE OF PUBLICATION OF THIS PACKAGE INSERT
February 2000

        HAPP102

Updated on this site: December 2004
Source: Community Pharmacy

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