Amiodarone
Drug Nomenclature
Amiodarone Hydrochloride
Drug Nomenclature
Pharmacopoeias. In China and Europe.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Amiodarone Hydrochloride). A white or almost white, fine crystalline powder. Very slightly soluble in water; sparingly soluble in alcohol; freely soluble in dichloromethane; soluble in methyl alcohol. Store at a temperature not exceeding 30°. Protect from light.
Adsorption. Amiodarone is known to be adsorbed by PVC, although the amount of adsorption has varied in different studies. A study using amiodarone hydrochloride 600 micrograms/mL in glucose 5% found that the concentration fell by 10% in 3 hours followed by a steady decrease to 60% of the initial concentration after 5 days when stored in flexible PVC bags at ambient temperature. However, another study using amiodarone hydrochloride 1.8 to 2 mg/mL in glucose 5% found only that the concentration remained 97.3% of the initial value after 24 hours in PVC infusion bags. In the first study, perfusion of the solution through PVC giving sets resulted in the concentration falling to 82% after 15 minutes, whereas the second study found the concentration fell to 95.1 % after 1 hour but then returned to the initial value. No loss was noted in either study when glass or rigid PVC containers were used, suggesting that the losses were caused by the plasticiser, di-2-ethylhexylphthalate (DEHP). Amiodarone may also leach out DEHP and other plasticisers, and it has been suggested that bags and tubing containing DEHP should not be used for giving amiodarone in order to minimise patient exposure.
Incompatibility. Amiodarone injection has been reported to be incompatible with aminophylline, flucloxacillin, heparin, and sodium bicarbonate. A further study reported incompatibility with ampicillin/sulbactam sodium, ceftazidime sodium, digoxin, furosemide, imipenem/cilastatin sodium, magnesium sulfate, piperacillin sodium, piperacillin/tazobactam sodium, potassium phosphate, and sodium phosphate. UK licensed product information states that it is incompatible with sodium chloride solutions.
Stability. An oral suspension prepared from tablets and containing amiodarone hydrochloride 5 mg/mL was stable for 3 months at 4° and 6 weeks at 25°.
Adverse Effects and Treatment
Adverse effects are common with amiodarone. Many are dose-related and reversible with reduction in dose; however, because of its long half-life this can take some time and adverse effects may develop after treatment is stopped.
Adverse cardiovascular effects associated with amiodarone include severe bradycardia, sinus arrest, and conduction disturbances. Severe hypotension may follow intravenous use, particularly (though not exclusively) at rapid infusion rates. Amiodarone may also produce ventricular tachyarrhythmias; torsade de pointes has been reported but appears to be less of a problem with amiodarone than other antiarrhythmics. Rarely, heart failure may be precipitated or aggravated. Amiodarone reduces the peripheral transformation of thyroxine (T4) to tri-iodothyronine (T3) and increases the formation of reverse-T3. It can affect thyroid function and may induce hypo- or hyperthyroidism. There have been reports of severe pulmonary toxicity including pulmonary fibrosis and interstitial pneumo-nitis. These effects are usually reversible on withdrawal of amiodarone but are potentially fatal. Amiodarone can adversely affect the liver. There may be abnormal liver function tests and cirrhosis or hepatitis; fatalities have been reported. Prolonged use of amiodarone causes the development of benign yellowish-brown corneal microdeposits in the majority of patients, sometimes associated with coloured haloes of light; these are reversible on stopping therapy. Photosensitivity reactions are also common and more rarely blue-grey discoloration of the skin may occur.
Other adverse effects reported include benign intracranial hypertension, haemolytic or aplastic anaemia, peripheral neuropathy, paraesthesias, myopathy, ataxia, tremor, nausea, vomiting, a metallic taste, nightmares, headaches, sleeplessness, fatigue, and epididymitis. Thrombophlebitis can occur if amiodarone is injected regularly or infused for prolonged periods into a peripheral vein. Rapid intravenous injection has been associated with anaphylactic shock, hot flushes, sweating, and nausea.
It has been suggested that amiodarone-induced phospholipidosis may explain some of its adverse effects. Amiodarone’s iodine content contributes to its thyrotoxicity.
Effects on electrolyte balance. Hyponatraemia associated with the syndrome of inappropriate secretion of antidiuretic hormone has been reported in patients taking amiodarone. In each case, the hyponatraemia improved when the dose was reduced or amiodarone was stopped.
Effects on the eyes. Slit-lamp examination showed corneal abnormalities in 103 of 105 patients treated with amiodarone for 3 months to 7 years. The most advanced abnormality comprised whorled patterns with uniform granular opacities. The corneal deposits became denser if amiodarone dosage was increased and regressed if dosage was reduced. Ocular symptoms were reported in only 12 patients. Photophobia was reported in 3 patients, while 2 had visual haloes, 1 had blurring of vision, and a further 6 had lid irritation. However, lid irritation was considered a photosensitive skin reaction and blurred vision was probably not due to amiodarone. No patient had any deterioration in visual acuity attributable to amiodarone. In 16 patients amiodarone was withdrawn with complete clearing of corneal abnormalities within 7 months and routine ophthalmological monitoring was considered unnecessary in patients without ocular symptoms. However, optic neuropathy and neuritis with visual impairment have been reported with amiodarone and UK licensed product information recommends that annual ophthalmological examinations should be performed.
A sicca syndrome with diminished tear and saliva production has been reported during amiodarone treatment.
Effects on the genitalia. Epididymal swelling and scrotal pain have been reported with amiodarone. Time to onset varied from 7 to 71 months after starting treatment, and resolution occurred within 10 weeks despite continuation of amiodarone in some patients. The mechanism of the reaction is unknown, but in 1 patient the concentration of desethylamiodarone in semen was fivefold that in serum.
Brown discoloration of semen and sweat has also been associated with amiodarone therapy
Effects on the heart. Amiodarone has the potential to provoke arrhythmias; it prolongs the QT interval and there have been reports of torsade de pointes. However, a review of the literature indicated that the frequency of proarrhythmic events was low. The risk of torsade de pointes also appears to be lower with amiodarone than with other class III antiarrhythmics, possibly due to additional actions of amiodarone such as blockade of calcium channels.
Effects on lipid metabolism. Amiodarone increases phos-pholipid concentrations in tissues and this may be responsible for some of its adverse effects. Although hyperlipidaemia may result from hypothyroidism, amiodarone can also increase serum-cholesterol concentrations independently of any effect on the thyroid. The effect on triglyceride concentrations is not clear.
Effects on the liver. Plasma concentrations of liver enzymes are often increased in patients taking amiodarone but this is usually asymptomatic. However, there have been reports of hepatic injury, including hepatitis and cirrhosis, with histological changes resembling alcoholic liver disease. Fatal cirrhosis has been reported, usually in patients receiving high doses or long-term therapy, and may develop after stopping amiodarone. However, rapidly progressive fatal hepatic failure has occurred only one month after starting treatment. There have also been reports of severe cholestasis, including a case that was reversible, and another that was fatal, despite amiodarone being stopped. Acute hepatitis occurring within 24 hours of intravenous amiodarone has been reported, but in 1 case did not recur with subsequent oral therapy, suggesting that the reaction may have been related to the vehicle used in the intravenous formulation.
Effects on the lungs. Pulmonary toxicity is one ofthe most severe adverse effects associated with amiodarone therapy. Reviews have suggested that it may occur in up to 10% of patients (although the incidence in controlled studies appears to be lower) and fatalities have been reported. The onset is usually chronic, and patients often present several months after starting amiodarone with increasing dyspnoea, cough, and pleuritic chest pain; however, the onset may also be more acute, and in one patient occurred within days of starting amiodarone. Acute reactions have also developed in patients undergoing surgery or other procedures; two patients with amiodarone pulmonary toxicity died less than 1 hour and 24 hours, respectively after pulmonary angiography. Different forms of toxicity have been reported, including interstitial and alveolar infiltration, fibrosis, and pneumonitis; amiodarone-induced asthma has also been reported. Although there is some evidence that toxicity is dose-related, it has also occurred at low doses, and different mechanisms may be involved; some patients have evidence of direct toxicity, while in others an immunological reaction appears to be involved. Most patients recover gradually if amiodarone is stopped, but treatment with corticosteroids may be given if necessary, and has been particularly recommended in acute lung injury.
Effects on mental state. There have been isolated reports of patients (age range 54 to 80 years) developing delirium within about 4 to 17 days of starting amiodarone therapy. Mental status improved on withdrawal of amiodarone.
Effects on the nervous system. Neurological toxicity is a recognised adverse effect of amiodarone. A study in 10 patients treated with amiodarone for more than 2 years found that 3 had evidence of peripheral neuropathy, possibly correlated with high doses and high serum concentrations of amiodarone.
Effects on the pancreas. Pancreatitis has been reported in a patient 4 days after starting amiodarone. Symptoms resolved after withdrawal ofthe drug but returned on re-exposure.
Effects on the skin and hair. The most common adverse skin reaction associated with amiodarone is photosensitivity. This is a phototoxic rather than a photoallergic reaction and the wavelengths responsible extend from the long-wave ultraviolet (UVA) into the visible light range. Affected patients should be advised to wear protective clothing and avoid exposure to sunlight. Topical sunblock preparations, such as those containing zinc or titanium oxides, may reduce the risk of reaction and a reduction in amiodarone dosage may also be useful. Although pyridoxine has been reported to protect against amiodarone-induced photosensitivity, results from a double-blind placebo-controlled study indicated that it may enhance the photosensitivity. Photosensitivity may continue for several weeks after withdrawal of amiodarone due to its extensive distribution, and persistence for longer periods has been reported. There have also been reports of basal cell carcinoma, possibly related to amiodarone-induced photosensitivity.
Blue-grey and golden-brown pigmentation of light-exposed skin have been reported during long-term amiodarone use. The pigmentation is usually slowly reversible on withdrawing amiodarone but may not completely disappear. The mean concentrations of amiodarone and its desethyl metabolite in light-exposed pigmented skin have been found to be 10 times the concentrations in non-exposed skin. Discoloration of semen and sweat has also been noted (see Effects on the Genitalia, above). Cutaneous vasculitis, exfoliative dermatitis, and fatal toxic epidermal necrolysis have been reported. Alopecia has been associated with amiodarone but increased hair growth, possibly due to the vasodilator activity of amiodarone, has also been reported. Extravasation of amiodarone injection has caused severe skin necrosis.
Effects on thyroid function. Amiodarone has complex effects on thyroid function and, while the majority of euthyroid patients receiving amiodarone remain clinically euthyroid, both hypo- and hyperthyroidism may occur. Amiodarone has direct effects on the thyroid gland, but also alters serum concentrations of thyroid hormones, complicating the interpretation of thyroid function tests. Use of amiodarone results in a reduction of the peripheral conversion of thyroxine (T4) to tri-iodothyronine (T3) with a resulting increase in T4, a modest fall in T3, and an increase in reverse-T3 concentrations; the basal serum-TSH (thyroid-stimulating hormone; thyrotrophin) concentration rises initially but tends to return to normal after about 3 months of treatment.
The prevalence of clinical hypo- and hyperthyroidism appears to correlate with dietary iodine intake, with hypothyroidism being more common in areas of adequate iodine intake and hyperthyroidism in areas of lower intake; the overall incidence of thyroid disorders has been suggested to be anywhere between 1 to 32%. Although the exact mechanism for the toxicity is not known, amiodarone has a high iodine content (about 75 mg of iodine in each 200-mg tablet) and the large iodine load may affect the thyroid, particularly in patients with an underlying subclinical thyroid defect. Auto-immune mechanisms may also contribute and antithyroid antibodies have been detected during amiodarone therapy. The high iodine load appears to be the main mechanism for hypothyroidism, but for hyperthyroidism two mechanisms may be involved. Type I amiodarone-induced thyrotoxicosis appears to be precipitated by the iodine load, whereas type II amiodarone-induced thyrotoxicosis is a destructive thyroiditis that is probably caused by a direct toxic effect on the thyroid gland. Assessment of thyroid function is recommended in patients before starting amiodarone treatment and periodically during treatment; TSH concentrations should be measured, along with free T3 and T4.
Amiodarone-induced hypothyroidism usually presents similarly to other forms of hypothyroidism and treatment is with levothyroxine, starting with a low dose and gradually increasing until control is achieved; amiodarone may be continued. Amiodarone-induced hyperthyroidism is a more complex problem and may be difficult to diagnose and manage. Patients may present with classical symptoms such as tachycardia, tremor, weight loss, nervousness, and irritability, but in other cases reappearance of angina, or a worsening of arrhythmia may be the only indication. Amiodarone is usually stopped if clinical hyperthyroidism develops, but may be continued if necessary while the hyperthyroidism is treated. Management depends on whether the patient has type I or type II hyperthyroidism. Treatment of type I is usually with the thiourea drugs carbimazole, thiamazole, or propylthiouracil; in resistant cases potassium perchlorate may be used with a thiourea to reduce the thyroid iodine load. Lithium carbonate has been used as an alternative, but its role is not yet established. In type II thyrotoxicosis, treatment is usually with corticosteroids, and they may also be used with thioureas where the type is mixed or unclear. Oral cholecystographic contrast media such as iopanoic acid have also been used, but appear to be less effective. Radio-iodine can be used but may not be effective if the uptake of radio-iodine by the thyroid is low due to the iodine load from amiodarone; radio-iodine has also been used to allow amiodarone to be restarted in patients with a history of amiodarone-induced hyperthyroidism. Thyroidectomy may have a role in the treatment of resistant amiodarone-induced hyperthyroidism.
Lupus. There have been reports of lupus developing in patients treated with amiodarone; the condition improved when amiodarone was stopped.
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