Amiodarone: Precautions, Interactions
Precautions
Amiodarone should not be given to patients with bradycardia, sinoatrial block, AV block or other severe conduction disorders (unless the patient has a pacemaker), severe hypotension, or severe respiratory failure. It may be used, but with caution, in patients with heart failure. Electrolyte disorders should be corrected before starting treatment. The use of amiodarone should be avoided in patients with iodine sensitivity, or evidence or history of thyroid disorders. Patients taking amiodarone should avoid exposure to sunlight. Thyroid function should be monitored regularly in order to detect amiodarone-induced hyper- or hypothyroidism. Thyroxine, tri-iodothyronine, and thyrotrophin (thyroid-stimulating hormone; TSH) concentrations should be measured; clinical assessment is important but is unreliable alone. See also Effects on Thyroid Function under Adverse Effects and Treatment, above.
Tests of liver and pulmonary function should also be carried out regularly in patients on long-term therapy. Ophthalmological examinations should be performed annually. Although urinary excretion is not a major route for the elimination of amiodarone or its metabolites, there is a possibility of iodine accumulation in renal impairment.
Intravenous injections of amiodarone should be given slowly: if prolonged or repeated infusions are envisaged, the use of a central venous catheter should be considered.
Some of the contra-indications for amiodarone may not apply when it is given intravenously in emergency situations.
Administration. For the problems of controlling the delivery rate of amiodarone by intravenous infusion, see under Uses and Administration, below.
Breast feeding. Amiodarone is distributed into breast milk and significant amounts may be ingested if infants are breast fed. Licensed product information therefore contra-indicates the use of amiodarone during breast feeding, and the American Academy of Pediatrics considers that the use of amiodarone may be of concern due to the risk of hypothyroidism in the infant. In one study, amiodarone was still detectable in breast milk several weeks after amiodarone was stopped, suggesting that caution is still required. However, there has been a report of an infant who was successfully breast fed with close monitoring of thyroid function; the mother stopped amiodarone at delivery.
Porphyria. Amiodarone is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in in-vitro systems.
Pregnancy. Each 200-mg tablet of amiodarone contains about 75 mg of iodine. The potential effect of this iodine load on the fetus has limited the use of amiodarone in pregnancy since iodine freely crosses the placenta and may cause thyroid disorders in the fetus. In addition, amiodarone and desethylamiodarone both cross the placenta, with respective concentrations in cord blood at delivery of about 10% and 25% of the maternal plasma concentrations, and direct effects on the fetus are therefore possible. However, a review of 64 reported cases of amiodarone use during pregnancy found no evidence of an increased incidence of fetal malformations; hypothyroidism occurred in 14 neonates (22%), but only 2 had detectable goitre, and 2 neonates had transient hyperthyroidism. Neurodevelopmental follow-up was limited, but mild abnormalities were reported in some cases; this appeared to be independent of thyroid status, suggesting it may have been due to a direct effect of amiodarone.
Interactions
Amiodarone should be used with caution with other drugs liable to induce bradycardia, such as beta Mockers or calcium-channel blockers, and with other anti-arrhythmic drugs. Use with arrhythmogenic drugs, particularly drugs that prolong the QT interval such as phenothiazine antipsychotics, tricyclic antidepressants, halofantrine, and terfenadine, should be avoided. Drugs that cause hypokalaemia or hypomagnesaemia may also increase the risk of arrhythmias with amiodarone. Amiodarone is metabolised by the cytochrome P450 isoenzymes CYP3A4 and CYP2C8 and interactions may occur with inhibitors of these enzymes, particularly with inhibitors of CYP3A4 such as HIV-protease inhibitors, cimetidine, and grapefruit juice. Enzyme inducers such as rifampicin and phenytoin may reduce amiodarone concentrations. In addition, amiodarone is an inhibitor of some cytochrome P450 isoenzymes, including CYP3A4 and CYP2D6, resulting in higher plasma concentrations of other drugs metabolised by these enzymes. Examples of these include ciclosporin, clonazepam, digoxin, flecainide, phenytoin, procainamide, quinidine, simvastatin, and warfarin. Amiodarone also inhibits P-glycoprotein and could affect drugs that are P-glycoprotein substrates.
Agalsidase. For the effect of the use of amiodarone with agalsidase alfa or beta.
Antibacterials. Palpitations and activation of an implantable cardioverter defibrillator occurred in a woman receiving amiodarone when rifampicin was added. Serum concentrations of amiodarone were reduced, probably due to induction of metabolising enzymes by rifampicin.
Antiepileptics. The interaction between phenytoin and amiodarone resulting in increased plasma-phenytoin concentrations is widely recognised. However, phenytoin is a hepatic enzyme inducer and has been reported to decrease serum-amiodarone concentrations by 32 and 49% after 1 and 2 weeks of use respectively.
Antivirals. A potential interaction has been suggested between amiodarone and HIV-protease inhibitors due to inhibition of amiodarone metabolism. Raised serum concentrations of amiodarone have been reported in a patient who received indinavir for postexposure prophylaxis; no clinical signs of toxicity occurred.
Grapefruit juice. A study in healthy subjects reported that grapefruit juice decreased the metabolism of amiodarone; the area under the plasma concentration-time curve (AUC) and the maximum plasma concentration of amiodarone were both increased.
Histamine H2-antagonists. Cimetidine inhibits hepatic metabolism and an increase in the serum-amiodarone concentration has been reported in 8 out of 12 patients given amiodarone and cimetidine.
Theophylline. For a report of increased serum-theophylline concentrations and resultant adverse effects in a patient when amiodarone was added to therapy, see Antiarrhythmics.
Pharmacokinetics
Amiodarone is absorbed variably and erratically from the gastrointestinal tract, the average bioavailability is about 50%, but varies widely, and both the rate and extent of absorption are increased by food. It is extensively distributed to body tissues and accumulates notably in fat as well as in skeletal muscles and highly perfused tissues such as liver, lungs, and spleen; it has been reported to be about 96% bound to plasma proteins. The terminal elimination half-life is about 50 days with a range of about 20 to 100 days due to its extensive tissue distribution. On stopping prolonged amiodarone therapy a pharmacological effect is evident for a month or more. A major metabolite, desethylamiodarone, has antiarrhythmic properties. There is very little urinary excretion of amiodarone or its metabolites, the major route of excretion being in faeces via the bile; some en-terohepatic recycling may occur. Amiodarone and desethylamiodarone are reported to cross the placenta and to be distributed into breast milk. After intravenous injection the maximum effect is achieved within 1 to 30 minutes and persists for 1 to 3 hours.
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