Darmil 100 Mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Darmil 100mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Darmil 100mg tablet contains 100mg Amiodarone Hydrochloride For excipients, see 6.1
3 PHARMACEUTICAL FORM
Tablet
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Amiodarone hydrochloride is indicated only for the treatment of severe rhythm disorders not responding to other therapies or when other treatments cannot be used. Treatment should be initiated and normally monitored only under hospital or specialist supervision.
Atrial flutter and fibrillation when other drugs cannot be used.
All types of tachyarrhythmias of paroxysmal nature including: supraventricular, nodal and ventricular tachycardias, ventricular fibrillation; when other drugs cannot be used.
Tachyarrhythmias associated with Wolff-Parkinson-White Syndrome. Tablets are used for stabilisation and long-term treatment.
4.2
Posology and Method of Administration
Paediatric population:
The safety and efficacy of amiodarone in children has not been established. Currently available data are described in sections 5.1 and 5.2
Adults:
It is particularly important that the minimum effective dose be used. In all cases the patient’s management must be judged on the individual response and well-being.
Initial Stabilisation
Treatment should be started with 200 mg, three times a day and may be continued for one week. The dosage should then be reduced to 200 mg, twice daily for a further week. The initial dose is needed in order to rapidly achieve adequate tissue levels.
Maintenance
After the initial period the dosage should be reduced to 200 mg daily, or less if appropriate. The scored 100 mg tablet to be should be used to titrate the minimum dosage required to maintain control of the arrhythmia. The Maintenance dosage should be regularly reviewed, especially in rare cases where the patient may require a higher maintenance dose and where this exceeds 200 mg daily.
It is particularly important that the minimum effective dosage is used and the patient is monitored regularly to detect clinical signs of excess Amiodarone dosage. Side effects can result from too high a dose during maintenance therapy.
Sufficient time must be allowed for new distribution equilibrium to be achieved between dosage adjustments (Amiodarone is strongly protein bound and has an average plasma half-life of fifty days).
Changeover from Intravenous to Oral Therapy
If patients are being switched from intravenous Amiodarone therapy, oral administration should be initiated concomitantly at the usual loading dose (200 mg three times a day) and then intravenous therapy gradually phased out.
Dosage reduction /withdrawal
Side effects slowly disappear as tissue levels fall. Following drug withdrawal, residual tissue bound Amiodarone may protect a patient for up to one month. However, the likelihood of the occurrence of arrhythmia during this period should be considered. In patients with potentially lethal arrhythmias the long half-life is an invaluable safeguard as omission of occasional doses is not significant regarding the overall therapeutic effect.
Elderly
It is important that the minimum effective dosage is used. Whilst there is no evidence that dosage requirements are different for the elderly, they may be more susceptible to bradycardia and conduction defects if too high a dose is employed. Particular attention should be paid it to monitoring thyroid function. See Contra-dictions, Warnings etc.
4.3 Contraindications
Sinus bradycardia and sino-atrial heart block. In patients with severe conduction disturbances (high grade AV block, bifascicular or trifascicular block) or sinus node disease, Amiodarone should be used only in conjunction with a pacemaker.
Where there is evidence or history of thyroid dysfunction. A thyroid function test should be performed prior to therapy in all patients.
Known hypersensitivity to iodine or to Amiodarone (one 100 mg tablet contains approximately 37.5mg iodine, one 200 mg tablet contains approximately 75 mg iodine).
The combination of Amiodarone with drugs which may prolong the QT interval and thereby induce Torsades de Pointes ventricular tachycardia is contra-indicated (see Drug Interactions section).
Amiodarone is contra-indicated in nursing mothers (see section 4.6, Pregnancy and Lactation).
4.4 Special warnings and precautions for use
High dosage: too high a dose of Amiodarone 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 treatment should be withdrawn. If necessary beta-adrenostimulants or glucagon may be given.
Amiodarone induces the following ECG changes: QT interval lengthening corresponding to prolonged repolarisation with the possible development of U and deformed T waves. These changes are evidence of its pharmacological action and do not reflect toxicity.
Heart failure: Amiodarone is not contra-indicated in patients with latent or manifest heart failure but caution should be exercised as, occasionally, existing heart failure may be worsened. In such cases, Amiodarone may be used with other appropriate therapies.
Hepatic effects: there have been no literature reports on the potentiation of hepatic adverse effects of alcohol, however, patients should be advised to moderate their alcohol intake while taking Amiodarone.
It is advised that the following precautions are observed:
Liver function studies particularly transaminases should be monitored before treatment and six-monthly thereafter.
Ophthalmological examination is recommended annually, unless blurred or decreased vision supervenes.
Patients should be carefully evaluated clinically and consideration given to chest X-ray; if pulmonary toxicity is suspected during treatment a chest X-ray and lung function testing should be obtained, including if possible measurement of transfer factor.
In patients with auto-immune thyroid disease the risks of thyroid dysfunction during amiodarone therapy are greater and the elderly are at particular risk; in these groups monitoring is recommended before the start of treatment, then six monthly and should be continued for some months after discontinuation of treatment.
4.5 Interaction with other medicinal products and other forms of interaction
Some of the more important drugs that interact with Amiodarone include warfarin, digoxin, phenytoin and any drugs which prolong the Q T interval.
Amiodarone raises the plasma concentrations of highly protein bound drugs, for example oral anticoagulants and phenytoin. The dose of warfarin should be reduced accordingly. More frequent monitoring of prothrombin time both during and after Amiodarone treatment is recommended. Phenytoin dosage should be reduced if signs of overdose appear, and plasma levels may be measured.
Administration of Amiodarone to a patient already receiving digoxin will bring about an increase in the plasma digoxin concentration and thus precipitate symptoms and signs associated with high digoxin levels. Monitoring is recommended and digoxin dosage usually has to be reduced. A synergistic effect on heart rate and atrioventricular conduction is also possible.
Combined therapy with any drug known to prolong the QT interval is contraindicated (see Contraindications section) due to the increased risk of Torsade de Pointes. They include the following:
E Class Ia anti-arrhythmic drugs e.g. Quinidine, procainamide, disopyramide
E Class III anti-arrhythmic drugs e.g. Solatol, bretylium E Intravenous erythromycin, co-trimoxazole or pentamidine injection E Anti-psychotics e.g. Chlorpromazine, thioridazine, pimozide, haloperidol
E Lithium and tricyclic anti-depressants e.g. Doxepin, maprotiline, amitriptyline
E Certain antihistamines e.g. Terfenadine, astemizole E Anti-malarials e.g. Quinine, mefloquine, halofantrine.
Combined therapy with the following drugs is not recommended:
Beta blockers and certain calcium channel inhibitors (diltiazem, verapamil); potentiation of negative chronotropic properties and conduction showing effects may occur.
Caution should be exercised over combined therapy with the following drugs which may cause hypokalemia: and/or hypomagnesaemia: diuretics, systemic corticosteriods, tetracosactrin, intravenous amphotericin.
Hypokalemia: corrective action should be taken and QT interval monitored.
Torsades de Points: antiarrhythmic agents should not be given; pacing may be instituted and IV magnesium may be used.
General anaesthesia: caution is advised, also in patients receiving high dose oxygen therapy. The anaesthetist should be informed that the patient is taking Amiodarone.
Potentially severe complications have been reported in patients taking Amiodarone undergoing general anaesthesia, such as bradycardia unresponsive to atropine, hypotension, disturbances of conduction, decreased cardiac output.
A few cases of adult respiratory distress syndrome, most often in the period immediately after surgery, have been observed. A possible interaction with the high oxygen concentration may be implicated.
Amiodarone may increase the plasma levels of cyclosporin when used in combination.
Pregnancy
There are insufficient data on the use of Amiodarone during pregnancy in humans to judge any possible toxicity. In view of the pharmacological properties of the drug on the foetus and its effects on the foetal thyroid gland, its administration in pregnancy should be avoided.
Lactation
Amiodarone is excreted into the breast milk in significant quantities and breast-feeding is contra-indicated.
4.7 Effects on ability to drive and use machines
None stated.
4.8 Undesirable effects
Due to possible serious adverse reactions affecting the lung, liver, thyroid gland, skin and peripheral nervous system, patients on long-term Amiodarone treatment should be carefully supervised. These reactions can also be delayed.
Pulmonary: Amiodarone can cause pulmonary toxicity (hypersensitivity pneumonitis, alveolar/interstitial pneumonitis or fibrosis, pleuritis, bronchiolitis obliterans organising pneumonia). Sometimes this toxicity can be fatal.
Presenting features can include dyspnoea (which may be severe and unexplained by the current cardiac status), non-productive cough and deterioration in general health (fatigue, weight loss and fever). The onset is usually slow but may be rapidly progressive. Whilst the majority of cases had been reported with long-term therapy, a few have occurred soon after starting treatment.
Patients should be carefully evaluated clinically and consideration given to chest X-ray before starting therapy. If pulmonary toxicity is suspected during treatment, this should be repeated and associated with lung function testing, including where possible measurement of transfer factor. Initial radiological changes may be difficult to distinguish from pulmonary venous congestion. Pulmonary toxicity has usually been reversible following early withdrawal of Amiodarone therapy, with or without corticosteriod therapy. Clinical symptoms often resolve within a few weeks followed by slower radiological and lung function improvement. Some patients can deteriorate despite discontinuing Amiodarone.
Adult respiratory distress syndrome has occurred in a few cases, most often in the period after surgery, resulting sometimes in fatalities (see Interactions).
Cardiac: bradycardia which is generally moderate and dose dependent has been reported. In some cases (sinus node disease, elderly patients) marked bradycardia or more exceptionally sinus arrest has occurred. There have been rare instances of conduction disturbances (sino-atrial block, various degrees of AV block). Because of the long half-life of Amiodarone, if bradycardia is severe and symptomatic the insertion of a pacemaker should be considered.
Amiodarone has a low proarrhythmic effect. However arrhythmia (new occurrence or aggravation), followed in some cases by cardiac arrest has been reported. Currently, it is not possible to differentiate a drug effect from the underlying cardiac condition or lack of therapeutic efficacy. This has usually occurred in combination with other precipitating factors particularly other antiarrhythmic agents, hypokalemia and digoxin.
Hepatic: Amiodarone may be associated with a variety of hepatic effects, including cirrhosis, hepatitis and jaundice. Some fatalities have been reported, mainly following long-term therapy. It is advisable to monitor liver function particularly transaminases before treatment and six monthly thereafter.
Elevation of serum transaminases can occur at the beginning of therapy (1.5 to 3 times normal). These may return to normal with dose reduction, or sometimes spontaneously.
Isolated cases of acute liver disorders with elevated serum transaminases and/or jaundice may occur; in such cases treatment should be discontinued.
Routine monitoring of liver function tests is advised. There have been reports of chronic liver disease. Alteration of laboratory tests which may be minimal (transaminases elevated 1.5 to 5 times normal) or clinical signs (possible hepatomegaly) during treatment for longer than six months should suggest this diagnosis. Abnormal clinical and laboratory test results usually regress upon cessation of treatment. Histological findings may resemble pseudo-alcoholic hepatitis, but they can be variable and include cirrhosis.
Thyroid: both hyper and hypothyroidism have occurred during, or soon after, Amiodarone treatment. Simple monitoring of the usual biochemical tests is confusing because some tests such as free T4 and free T3 may be altered when the patient is euthyroid. Clinical monitoring is therefore recommended before start of treatment, then six monthly and should be continued for some months after discontinuation of treatment. This is particularly important in the elderly. In patients whose history indicates an increased risk of thyroid dysfunction, regular assessment is recommended.
Hyperthyroidism: clinical features such as weight loss, asthenia, restlessness, increase in heart rate, recurrence of the 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) 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 Amiodarone therapy should be withdrawn. Clinical recovery usually occurs within a few weeks, although severe cases, sometimes resulting in fatalities, have been reported.
Courses of anti-thyroid drugs 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 corticosteriod therapy (eg 1 mg/kg prednisolone) may be required for several weeks.
Hypothyroidism: clinical features such as weight again, reduced activity or excessive bradycardia should suggest the diagnosis. This may be supported by an elevated serum TSH level and an exaggerated TSH response to TRH. T4 and T3 levels may be low.
Thyroid hypofunction usually resolves within three months of cessation of therapy; it may be treated cautiously with L-thyroxine. Concomitant use of Amiodarone should be continued only in life-threatening situations, when TSH levels may provide a guide to L-thyroxine dosage.
Ophthalomological: patients on continuous therapy almost always develop microdeposits in the cornea. The deposits are usually only discernible by slit-lamp examinations and may rarely cause subjective symptoms such as a visual haleos and blurring of vision. The deposits are considered essentially benign, do not require discontinuation of Amiodarone and regress following termination of treatment. Rare cases of impaired visual acuity due to optic neuritis have been reported, although at present, the relationship with Amiodarone has not been established. Unless blurred or decreased vision occurs, ophthalomological examination is recommended annually.
Dermatological: patients taking Amiodarone can become unduly sensitive to sunlight and should be warned of this possibility. In most cases, the symptoms are limited to tingling, burning and erythema of sun exposed skin but severe phototoxic reactions with blistering may be seen. Photosensitivity may persist for several months after discontinuation of Amiodarone. Photosensitivity can be minimised by limiting exposure to UV light, wearing suitable protective hats and clothing and by using a broad spectrum sun screening preparation. Rarely, a slate grey or blue discolouration of light exposed skin, particularly on the face, may occur. Resolution of this pigmentation may be very slow once the drug is discontinued. Other types of skin rashes including isolated cases of exfoliative dermatitis have also been reported. Cases of erythema have been reported during radiotherapy.
Neurological: peripheral neuropathy can be caused by Amiodarone. Myopathy has occasionally been reported. Both these conditions may be severe although they are usually reversible on drug withdrawal. Nightmares, vertigo, headaches, sleeplessness and paraesthesia may also occur. Tremor and ataxia have also infrequently been reported usually with complete regression after reduction of dose or withdrawal of the drug. Benign intracranial hypertension (pseudo-tumor cerebri) has been reported.
Other: other unwanted effects occasionally reported include nausea, vomiting, metallic taste (which usually occur with loading dose and which regress on dose reduction), fatigue, impotence, epididymo-orchitis and alopecia. Isolated cases suggesting a hypersensitivity reaction involving vasculitis, renal involvement with moderate elevation of creatinine levels or thrombocytopenia have been observed. Haemolytic or aplastic anaemia have rarely been reported.
4.9 Overdose
Amiodarone has been shown in a animal studies to have a high LD50, hence it is unlikely that a patient will ingest an acute toxic dose. In such an event gastric lavage may be employed to reduce absorption in addition to general supportive measures. Neither Amiodarone nor its metabolites are dialysable. The patient should be monitored and if bradycardia occurs, beta-adrenostimulants or glucagon may be given. Spontaneously resolving attacks of ventricular tachycardia may also occur. Due to the pharmacokinetics of Amiodarone (long half-life), adequate and prolonged surveillance of the patient, particularly cardiac status, is recommended.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Amiodarone hydrochloride is an antiarrhythmic.
No controlled paediatric studies have been undertaken.
In published studies the safety of amiodarone was evaluated in 1118 paediatric patients with various arrhythmias. The following doses were used in paediatric clinical trials.
Oral
- Loading dose: 10 to 20mg/kg/day for 7 to 10 days (or 500 mg/m /day if expressed per square meter)
- Maintenance dose: the minimum effective dosage should be used; according to individual response, it may range between 5 to 10 mg/kg/day
(or 250 mg/m2/day if expressed per square meter)
5.2
Pharmacokinetic Properties
Amiodarone is strongly protein bound and has an average plasma half-life of 50 days. There may be considerable inter-patient variation with half-life values ranging from less than 20 days to more than 100 days having been reported. High initial doses of Amiodarone, for example 600mg/day, should be given to achieve effective tissue levels as rapidly as possible. Owing to the long half-life of the drug, a maintenance dose of only 200mg/day, or less is usually necessary. Sufficient time must be allowed for a new distribution equilibrium to be achieved between adjustments of dose.
The long half-life is a valuable safeguard for patients with potentially lethal arrythmias as omission of occasional doses does not significantly influence the protection afforded by an Amiodarone.
No controlled paediatric studies have been undertaken. In the limited published data available in paediatric patients, there were no differences noted compared to adults.
5.3 Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
The following inactive ingredients are used: Lactose Monohydrate, Pregelatinised Starch, Povidone, Colloidal Anhydrous Silica, Maize Starch, Magnesium Stearate.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25°C. Store in the original package.
6.5 Nature and contents of container
Lithographed carton boxes containing PVC/Al blister strips of tablets. Each box contains a patient information leaflet.
Pack Size: 28 tablets.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
The Co-operative Pharmacy National Distribution Centre Limited
Enterprise Way
Meir Park
Stoke on Trent
ST3 7UN
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 01805/0025
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
23/03/2009
10 DATE OF REVISION OF THE TEXT
30/12/2011
11 DOSIMETRY (IF APPLICABLE)
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)