Date of approval.
Date of modification.
® ®
Amiodarone Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
[Drug Name].
Generic name: Amiodarone Hydrochloride Tablets
English name: Amiodarone Hydrochloride Tablets
Hanyu Pinyin: Yansuan Andiantong Pian
Ingredients
The main ingredient of this product is: amiodarone hydrochloride
Chemical name: (2-butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone hydrochloride
Chemical structure formula.
Molecular formula: C25H29I2NO3-HCl
Molecular weight: 681.78
[Properties]: This product is a white-like round tablet, with an indentation in the middle of one side.
Indications
For severe arrhythmias for which other treatments are ineffective or other treatments are inappropriate.
1. atrial arrhythmias (atrial flutter, conversion of atrial fibrillation; maintenance of sinus rhythm after conversion).
2. nodal arrhythmias.
3. ventricular arrhythmias (treatment of life-threatening ventricular presystole and ventricular tachycardia and prevention of ventricular tachycardia or ventricular fibrillation).
4. arrhythmias with W-P-W syndrome.
Based on its pharmacological characteristics, amiodarone is suitable for the above arrhythmias, especially in combination with organic heart disease (coronary artery supply deficiency and heart failure).
Specification】0.2g
Dosage]
Loading dose.
Usually 600 mg (3 tablets) per day, which can be applied continuously for 8-10 days.
Maintenance dose.
It is advisable to apply the minimum effective dose, which can be given as 100-400 mg (1/2-2 tablets)/day depending on individual response, or 200 mg (1 tablet)/every other day or 100 mg (1/2 tablet)/day due to the prolonged therapeutic effect of amiodarone.
[Adverse effects].
Adverse reactions were classified according to organ system and incidence, where the classification categories of incidence were.
Very common (≥10%); Common (≥1%, < 10%); Uncommon (≥0.1%, < 1%); Rare (≥0.01%, < 0.1%); Very rare (< 0.01%); Unknown (not determinable based on available data).
Ocular abnormalities.
Very common: Corneal microdeposits, usually confined to the subpupillary area, are very common in adults who have been taking the drug consistently for more than 6 months and are not a contraindication to treatment. In exceptional cases, they may be accompanied by colored dazzling halos, photophobia, dry eye, or blurred vision. This corneal microdeposition consists of complex lipid deposits and is usually completely reversible after discontinuation of amiodarone treatment.
Very rare: optic neuropathy (optic neuritis) with blurred vision, vision loss, corneal degeneration, photosensitivity, ocular discomfort, dark spots, and crystal clouding. Macular degeneration or fundus optic papilloedema has also been reported, which can lead to varying degrees of visual acuity reduction and subsequent progression to blindness. At present, the relationship between this optic neuropathy and amiodarone is not clear. However, in the absence of other obvious etiologies, suspension of amiodarone administration is recommended.
Skin abnormalities.
Very common: photosensitivity reactions. During amiodarone treatment, patients are advised to avoid exposure to sunlight (and UV light).
Common: Patients develop lavender or blue-gray pigmentation of the skin during daily high-dose long-term treatment; this pigmentation will slowly disappear after treatment is stopped (10-24 months).
Very rare.
Erythema that appears during radiation therapy.
Spontaneous petechiae.
Rash, usually non-specific.
Exfoliative dermatitis, although the interrelationship between exfoliative dermatitis and amiodarone has not been established.
Alopecia.
Unknown: Severe skin reactions, sometimes fatal, especially dermatitis herpetiformis, toxic epidermal necrolysis, Stevens-Johnson syndrome, drug rash with eosinophilia, urticaria, and eczema.
Thyroid abnormalities.
Very common.
An “isolated” abnormality in thyroid hormone levels (increased T4 levels and normal or slightly decreased T3 levels) may occur in the absence of clinical manifestations of thyroid dysfunction and is not an indication for discontinuation of the drug.
Common.
Hypothyroidism with the following typical symptoms: weight gain, chills, apathy, lethargy; if there is a clear increase in TSH, the diagnosis is supported. Thyroid function can gradually return to normal within 1-3 months after discontinuation of amiodarone therapy; discontinuation of therapy is not mandatory, and if amiodarone therapy is indicated, L-thyroxine replacement therapy can be applied in combination with amiodarone therapy, using the TSH level as a guide for the dose administered.
Hyperthyroidism is even more misleading: patients are rarely symptomatic (mild unexplained weight loss, reduced effect of anti-anginal and/or anti-arrhythmic therapy); in older patients it manifests as mental disturbance or even as thyrotoxicosis. A definite decrease in ultrasensitive TSH levels supports the diagnosis and amiodarone must be discontinued: recovery is usually possible within 3-4 months after discontinuation. Severe cases can sometimes lead to death and require emergency treatment.
If thyrotoxicosis is suspected, either for thyroid reasons per se or for thyroid-induced myocardial imbalance, treatment with corticosteroids (1 mg/kg) can be administered directly for a sufficiently long time (3 months) due to the unstable effect of synthetic antithyroid drugs. Cases of hyperthyroidism have been reported several months after discontinuation of amiodarone therapy.
Pulmonary abnormalities.
Common.
Diffuse interstitial or alveolar lung disease and occlusive fine bronchiectasis with mechanized pneumonia (BOOP), sometimes fatal cases have been reported. If shortness of breath or dry cough after activity occurs, either in isolation or with worsening systemic status (fatigue, weight loss, fever), a chest x-ray is required if suspicious. If necessary, amiodarone therapy needs to be discontinued. These forms of lung disease can actually progress to pulmonary fibrosis.
Early discontinuation of amiodarone can restore this abnormality, whether or not it is associated with corticosteroid therapy. Clinical symptoms usually resolve within 3 or 4 weeks, with subsequent radiographic and pulmonary function improvement usually slower (over several months).
Some cases of pleurisy have been reported, which is generally associated with interstitial lung disease.
Very rare.
Bronchospasm, especially in patients with asthma.
Acute respiratory distress syndrome (sometimes fatal) has been reported, usually in the immediate postoperative period (possibly interacting with high oxygen concentrations) (see Precautions).
Unknown: Cases of pulmonary hemorrhage presenting as hemoptysis have been reported, and these pulmonary reactions are usually associated with amiodarone induced lung disease.
Neurological abnormalities.
Common.
Discomfort, weakness, tremor, involuntary movements, lack of coordination, gait abnormalities/ataxia, or other extrapyramidal symptoms.
Sleep disturbances, headaches, nightmares, hypersexuality.
Sensory, motor, or mixed peripheral neuropathy.
Uncommon.
Myopathy.
Sensory, motor, or mixed peripheral neuropathy and/or myopathy may appear several months and sometimes years after amiodarone treatment. Recovery of these symptoms usually begins within a few months of stopping amiodarone treatment, but is sometimes very slow and incomplete.
Very rare.
Cerebellar ataxia.
Benign intracranial hypertension (pseudotumor cerebri). If isolated headaches are present, a systematic examination is needed to identify the underlying cause.
Unknown: Demyelinating polyneuropathy, Parkinson’s disease, olfactory abnormalities.
Psychiatric abnormalities.
Unknown: mental confusion, delirium, hallucinations.
Hepatic abnormalities.
Cases of impaired liver function due to amiodarone have been reported: diagnosis can be made by increased serum transaminases. The following abnormalities have been reported.
Very common: isolated elevated serum transaminases, usually moderately elevated (1.5-3 times the normal range), which recover after downward adjustment of the administered dose, or even spontaneously.
Common: Acute abnormal liver function with high serum transaminases and/or jaundice, sometimes fatal, requiring discontinuation of amiodarone therapy.
Very rare: chronic liver function abnormalities (sometimes fatal) that occur during long-term treatment with amiodarone. Histological examination supports pseudo-alcoholic hepatitis, cirrhosis, with clinical and biological features exhibiting dissociated characteristics (irregular hepatomegaly, increased serum transaminases with values between 1.5 and 5 times the normal range), and such cases require regular liver function tests. If, after more than 6 months of amiodarone treatment, the patient shows a moderate increase in serum transaminases, then chronic liver impairment should be considered. Clinical and biochemical parameters usually recover after amiodarone therapy is discontinued. Some cases of irreversible liver damage have also been reported.
Cardiac abnormalities.
Common: generally moderate, dose-dependent bradycardia, congestive heart failure.
Uncommon: hypotension, conduction abnormalities (sinus atrial block with varying degrees of conduction block). Episodes or worsening of arrhythmias, sometimes accompanied by cardiac arrest.
Very rare: significant bradycardia, very rare reports of sinus arrest (sinus node insufficiency, elderly patients).
Unknown: tip-twist ventricular tachycardia (see “Precautions” and “Drug Interactions”).
Gastrointestinal abnormalities.
Very common: benign gastrointestinal abnormalities (nausea, vomiting, taste disturbances, anorexia and constipation), usually occurring at loading doses and disappearing with dose reductions.
Common: abdominal pain, taste abnormalities unknown: pancreatitis/acute pancreatitis, dry mouth.
Reproductive system abnormalities.
Very rare: epididymitis, impotence, hypoactive libido. The interrelationship between these disorders and amiodarone has not been established.
Vascular abnormalities.
Common: facial flushing.
Very rare: vasculitis.
Unknown: angioneurotic edema (Quincke’s edema).
Abnormal laboratory findings.
Rare: Rare hyponatremia may suggest syndrome of dysregulated secretion of antidiuretic hormone (SIADH).
Very rare: impaired renal function with moderately increased creatinine.
Hematologic and lymphatic system abnormalities.
Common: coagulation abnormalities.
Very rare: thrombocytopenia, hemolytic anemia, aplastic anemia.
Unknown: leukopenia, granulocyte deficiency.
Endocrine abnormalities.
Very rare: syndrome of dysregulated secretion of antidiuretic hormone (SIADH), especially in combination with drugs that cause hyponatremia. See also “Abnormalities in laboratory tests”.
Systemic abnormalities.
Unknown: Granulomas, including myeloid granulomas.
Immune system abnormalities.
Unknown: Allergic or anaphylactic-like reactions (including shock).
Metabolic and nutritional abnormalities.
Unknown: loss of appetite.
Musculoskeletal and connective tissue abnormalities.
Unknown: Lupus-like syndrome.
[Contraindicated].
Sinus bradycardia and sinus atrioventricular block without a pacemaker.
Sick sinus node syndrome without a pacemaker (risk of sinus arrest).
severe atrioventricular conduction abnormalities without a pacemaker.
hyperthyroidism, due to the possible worsening of hyperthyroidism by amiodarone.
Known hypersensitivity to iodine, amiodarone or excipients thereof.
Pregnancy, especially in the middle and second trimesters.
Lactation.
Combined application of the following drugs with the potential to induce tip-twisting ventricular tachycardia.
– Class Ia antiarrhythmic drugs (quinidine, hydroquinidine, propiamine).
– Class III antiarrhythmic drugs (sotalol, dofetilide, ibrit), the
– Non-antiarrhythmic drugs such as bendrotil, cisapride, diphenhydramine, erythromycin (administered intravenously), imipramine
moxifloxacin, moxifloxacin, spiramycin (intravenous administration), vincristine (intravenous administration), etc. (see Drug Interactions).
– sutropil.
-Psychosuppressant, pentazocine (intravenous).
Precautions]
Special Warnings
Cardiac abnormalities
ECG and serum potassium must be checked before starting amiodarone treatment, and ECG monitoring is recommended during treatment.
In elderly patients, the heart rate may be significantly slowed.
The pharmacological effects of amiodarone can induce ECG changes such as prolongation of the QT interval (associated with prolonged repolarization), which may be accompanied by U waves; this is a sign of reaching therapeutic concentrations and not a toxic effect.
Treatment should be discontinued if second or third degree AV block, sinus conduction block or double branch block is present. If a degree I AV block is present, close monitoring is required.
New arrhythmias have been reported to occur with amiodarone application, and pre-existing, treated arrhythmias may also deteriorate, sometimes fatally. In such cases, it is important but also difficult to distinguish between the ineffectiveness of the drug and the arrhythmogenic effect of the drug itself, whether or not it is associated with deterioration of cardiac function. (See Adverse Reactions).
The arrhythmogenic effects of amiodarone are rarer than those of other antiarrhythmic drugs and are generally seen in situations that cause prolongation of the QT interval, such as in combination with certain drugs (see Drug Interactions), and/or electrolyte balance disturbances. Despite the prolongation of the QT interval, the effect of amiodarone to induce tip-twisting ventricular tachycardia is low.
In particular, elevated ventricular defibrillation and/or pacing thresholds of pacemakers or implantable cardioverter-defibrillators have been reported with prolonged use of antiarrhythmic drugs, potentially compromising the efficacy of these treatments. Therefore, repeated validation of the function of the implanted device before and during treatment with amiodarone is recommended.
The potential risks and benefits of amiodarone administration must be carefully evaluated in patients with thyroid dysfunction, in whom arrhythmia progression or worsening of arrhythmias may occur.
Severe bradycardia.
Cases of severe, life-threatening bradycardia and heart block have been observed when amiodarone is administered in combination with sofibuvir alone or with other direct-acting hepatitis C virus (HCV) antivirals (DAA) such as daclatasvir, simeprevir, or ledipavir. Therefore, the combination of amiodarone with these drugs is not recommended.
If co-administration with amiodarone is unavoidable, close monitoring of the patient at the time of initiation of sofibuvir or in combination with other DAAs is recommended. If the patient is at high risk of developing severe bradycardia, the patient should be clinically monitored continuously for at least 48 hours after initiation of combination sofosbuvir therapy in an appropriate clinical setting.
Due to the long half-life of amiodarone, appropriate clinical monitoring should be performed in patients who have received amiodarone in the past several months and have discontinued amiodarone therapy and in patients who are about to start sofibuvir monotherapy or combination therapy with other DAAs.
When patients receive these propecia drugs in combination with amiodarone, with or without other heart rate lowering drugs, they should be cautioned about symptoms of bradycardia or heart block and should be advised to seek emergency medical advice if symptoms of bradycardia and heart block occur.
Abnormal thyroid function
Amiodarone can cause thyroid abnormalities, particularly in elderly patients and in patients with a history of thyroid disease. In patients with clinically normal thyroid function, amiodarone inhibits the peripheral conversion of thyroxine (T4) to triiodothyronine (T3), which can result in elevated thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3). The drug is also a potential source of large amounts of inorganic iodine. Due to its release of inorganic iodine, or for other reasons, amiodarone can cause both hypothyroidism and hyperthyroidism.
Thyroid function should be monitored prior to treatment and periodically thereafter. Because of the slow clearance of amiodarone and its metabolites, abnormal plasma hyperiodide levels, changes in thyroid function, and thyroid function test results may persist for weeks or even months after amiodarone is discontinued.
Clinical and biological monitoring of TSH is recommended in all patients before, during, and for several months after amiodarone therapy is discontinued, especially in elderly patients, patients with a history of thyroid nodules, goiter, or other thyroid dysfunction, and in addition, TSH testing is required in cases of clinically suspected thyroid dysfunction (see Adverse Reactions). Because of the slow clearance of amiodarone and its metabolites, abnormal plasma hyperiodide levels, changes in thyroid function, and abnormal thyroid function test results may persist for weeks or even months after discontinuation of the drug.
The presence of iodine in the drug can interfere with certain thyroid tests (binding to radioactive iodine, PBI); however, assessment of thyroid function is still feasible (T3, T4, TSHus).
Clinical reports of hypothyroidism have been published, and the disease can be identified by associated clinical symptoms and laboratory tests (especially elevated serum TSH levels). In some patients treated with amiodarone who are clinically hypothyroid, free thyroxine index values may be normal. Hypothyroidism is best treated by lowering the dose of amiodarone and/or by thyroid hormone supplementation. However, treatment must be individualized and in some patients it may be necessary to discontinue amiodarone.
Hyperthyroidism has been reported in patients treated with amiodarone, and the incidence may be higher in patients with inadequate prior dietary iodine intake. Amiodarone induced hyperthyroidism is usually more harmful than amiodarone induced hypothyroidism
It is more hazardous than amiodarone induced hypothyroidism because of the possibility of progression or worsening of thyrotoxicosis and/or cardiac arrhythmias, all of which may lead to death. Deaths associated with amiodarone induced thyrotoxicosis have been reported. The possibility of hyperthyroidism needs to be considered if any new arrhythmias develop.
The diagnosis of hyperthyroidism can be confirmed by the associated clinical signs, symptoms and laboratory tests, usually with an abnormally high serum T3 level (RIA method i.e. radioimmunoassay), a further increase in serum T4 and a decrease in serum TSH level (a sufficiently sensitive TSH assay should be used). a low TSH response in the TRH excitation test can be used for the diagnosis of hyperthyroidism, and this method can also be used in suspected cases. method can also be used for the diagnosis of suspected cases. Since patients with amiodarone-induced hyperthyroidism may have worsening arrhythmias, aggressive drug therapy should be necessary, and if possible, the amiodarone dose should be reduced or discontinued.
In patients with amiodarone-induced thyrotoxicosis, treatment with antithyroid agents, beta-adrenergic blockers and/or transient corticosteroids may be necessary. The onset of action of antithyroid medications may be particularly delayed because of the large amount of preformed thyroid hormones stored in the gland. Radioiodine therapy is contraindicated because amiodarone induced hyperthyroidism is associated with excessively low radioiodine uptake. Amiodarone-induced hyperthyroidism may be followed by transient hypothyroidism.
When aggressive treatment of amiodarone-induced thyrotoxicosis fails, or when amiodarone cannot be discontinued because it is the only effective drug for intractable arrhythmias, then surgical treatment may be an option. There is limited experience with the application of thyroidectomy in such patients, and this treatment modality can induce thyroid crisis. Therefore, careful surgical planning and anesthetic management are required.
There have been post-marketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone.
Pulmonary Toxicity
Post-marketing studies have reported acute (days to weeks) lung injury in patients treated with oral amiodarone (with or without initial intravenous amiodarone administration). This includes radiographic findings of pulmonary infiltrates and/or lung masses, alveolar hemorrhage, pleural effusions; bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxemia. In some patients, the disease progressed to respiratory failure and/or death. Although post-marketing reports have reported cases of pulmonary toxicity in patients treated with low doses of amiodarone; however, reports indicate that the use of lower loading and maintenance doses of amiodarone is associated with a reduced incidence of amiodarone induced pulmonary toxicity.
Amiodarone tablets can cause cough and progressive dyspnea, which may be accompanied by functional, imaging, gallium scan, and pathologic findings consistent with a diagnosis of pulmonary toxicity. Therefore, chest radiography, pulmonary function tests (including diffusion function) should be performed when starting treatment with amiodarone. Patients should be seen every 3-6 months for follow-up history taking, physical examination and chest radiography.
Pulmonary toxicity secondary to amiodarone appears to result from either indirect toxicity in the form of allergic pneumonia (including eosinophilic pneumonia) or direct toxicity in the form of interstitial/alveolar pneumonia.
In patients with pre-existing lung disease, the prognosis is poor if pulmonary toxicity is present.
Allergic pneumonia usually appears early in treatment, and reintroduction of amiodarone in these patients can lead to a rapid recurrence of the disease with increased severity. Bronchoalveolar lavage is an optional procedure to confirm this diagnosis, which is made when T-suppressive/cytotoxic (CD8-positive) lymphocytes are found. Treatment with steroids and discontinuation of amiodarone should be performed.
Once amiodarone induced interstitial/alveolar pneumonia is diagnosed, amiodarone should at least be reduced or preferably discontinued to promote recovery from pneumonia, especially when other acceptable antiarrhythmic therapies are available.
In patients treated with amiodarone, any new respiratory symptoms may indicate the presence of pulmonary toxicity and should be repeated with history, physical examination, chest radiography and pulmonary function measurements (and diffusion function) and evaluated.
Discontinuation of amiodarone therapy for suspected drug-induced pulmonary toxicity should be done with caution in patients presenting with life-threatening arrhythmias because the most common cause of death in these patients is sudden cardiac death. Therefore, before discontinuing amiodarone in these patients, every effort should be made to exclude other causes of respiratory compromise (e.g., congestive heart failure, application of Swan-Ganz catheterization if necessary, respiratory tract infection, pulmonary embolism, malignancy, etc.). In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where there is no applicable alternative therapy.
If the diagnosis of amiodarone induced allergic pneumonia is confirmed, then amiodarone should be discontinued and steroid therapy should be initiated. If amiodarone induced interstitial/alveolar pneumonia is diagnosed, then steroid therapy should be initiated and preferably amiodarone should be discontinued, or at least the amiodarone dose should be reduced. Some cases of amiodarone induced interstitial/alveolar pneumonia may resolve after a reduction in amiodarone dose and in combination with steroids. In some patients, re-dosing at lower doses does not result in recurrence of interstitial/alveolar pneumonia; however, in some patients (most likely due to severe alveolar injury), lung injury is irreversible.
Early discontinuation of amiodarone may allow recovery of symptoms. Therefore, treatment with amiodarone needs to be re-evaluated and hormonal therapy should be considered.
In rare cases, severe respiratory complications (adult acute respiratory distress syndrome) have occurred immediately after surgery and are sometimes fatal. It may be related to the interaction of high oxygen concentrations.
Liver injury
Regular monitoring of liver function is recommended at the initiation of amiodarone therapy and should then be performed periodically throughout the duration of amiodarone therapy (see ADVERSE REACTIONS). Both acute liver disease (including severe hepatocellular insufficiency or liver failure, sometimes fatal) and chronic liver disease can occur within 24 hours of intravenous administration with both oral and intravenous administration. Therefore, if transaminases increase more than three times the normal range or if liver enzyme levels multiply in patients who are already elevated at baseline, the dose of amiodarone needs to be reduced or treatment discontinued.
Elevated liver enzyme levels are frequently observed in patients treated with amiodarone, and most patients are asymptomatic.
The clinical and biological signs of chronic liver disease due to oral amiodarone can be very mild (hepatomegaly, transaminases up to 5 times the normal range) and recover after discontinuation of treatment, but fatal cases have been reported. In the few cases where biopsies have been performed, the histological picture resembles that of alcoholic hepatitis or cirrhosis. In patients treated with amiodarone, liver failure is a rare cause of death.
Neuromuscular abnormalities
Amiodarone can cause sensory, motor, or mixed peripheral neuropathy and myopathy (see Adverse Reactions).
Ocular abnormalities
Cases of optic neuropathy and/or optic neuritis have been reported in patients treated with amiodarone, and these disorders usually result in impaired vision. In some cases, the visual impairment progressed to permanent blindness. Optic neuropathy and/or optic neuritis can present at any time after the start of treatment. The causal relationship with medications has not been clearly established.
A complete ophthalmologic evaluation, including fundus observation, must be performed immediately upon the onset of visual blurring or the appearance of vision loss. In the event of amiodarone induced neuropathy or optic neuritis, it is necessary to discontinue amiodarone therapy because of the risk of progression to blindness (see Adverse Reactions).
Severe maculopapular reactions
Amiodarone therapy must be discontinued immediately if signs or symptoms of toxic epidermal necrolysis, Stevens-Johnson syndrome (e.g., progressive rash usually accompanied by blistering or mucosal lesions) are present.
Precautions
Combinations with the following drugs (see Drug Interactions).
Amiodarone may be used in combination with beta-blockers, except sotalol (prohibited).
Diltiazem and verapamil. Combinations should only be considered in the prophylaxis of potentially life-threatening ventricular arrhythmias.
Because amiodarone contains lactic acid, the drug is contraindicated in patients with congenital galactosemia, glucose and galactose malabsorption syndrome, or lactase deficiency.
Precautions for use
Electrolyte disturbances, especially hypokalemia: Pay attention to conditions prone to hypokalemia, which may promote the development of arrhythmogenic effects. Hypokalemia should be corrected prior to amiodarone administration.
The adverse reactions mentioned below are usually associated with high drug doses and can be avoided or their severity minimized by strict selection of the minimum maintenance dose.
During treatment, patients should be advised to avoid exposure to sunlight or to take sun protection measures.
The safety and efficacy of amiodarone in children have not been evaluated in controlled clinical trials.
Anesthesia
The anesthesiologist should be informed that the patient is receiving amiodarone prior to the patient undergoing surgical treatment.
In terms of adverse effects, prolonged use of amiodarone predisposes individuals under general or local anesthesia to hemodynamic instability, including bradycardia, hypotension, decreased cardiac output, and conduction disturbances.
In addition, some cases of acute respiratory distress syndrome have been observed in patients treated with amiodarone in the immediate postoperative period. Therefore, these patients should be closely monitored during artificial respiration (see Adverse Reactions).
Implantable cardiac devices
In patients with implantable defibrillators or pacemakers, the long-term use of antiarrhythmic drugs may affect pacing or defibrillation thresholds. Therefore, pacing and defibrillation thresholds should be evaluated at the start of and during treatment with amiodarone.
Laser Corneal Refractive Surgery
Patients should be informed that most laser keratomileusis devices are contraindicated in patients treated with amiodarone.
Pregnant women and nursing mothers
Pregnancy
Animal studies have not shown any teratogenic effects of this drug. Because of the lack of teratogenic effects in animals, it is not expected that the drug will have teratogenic effects in humans. To date, studies in humans and animals have shown that substances that cause malformations in humans also show teratogenic effects in animals.
In clinical situations, there are not enough relevant data to assess the possible teratogenic effects of amiodarone for its application during the first trimester of pregnancy.
Since from the 14th week of amenorrhea, the fetal thyroid gland begins to bind iodine, an effect on the fetal thyroid not expected in previous applications, iodine overload due to the application of this drug after this period can cause biological or clinical (goiter) hypothyroidism in the fetus.
Hypothyroidism or hyperthyroidism in the newborn: Amiodarone may cause harm to the fetus when administered to a pregnant woman. Although the use of amiodarone during pregnancy is uncommon, there have been a few published reports of congenital goiter/hypothyroidism and hyperthyroidism.
Therefore, this drug is contraindicated during the middle and second trimesters of pregnancy.
In general, amiodarone should be used during pregnancy only if the potential benefit to the mother outweighs the unknown risk to the fetus. If amiodarone is used during pregnancy or if the patient becomes pregnant while taking amiodarone, the patient should be informed of the potential hazard to the fetus.
Lactation
Amiodarone and its metabolites, as well as iodine, can be secreted in breast milk at higher concentrations than in maternal plasma. Because of the risk of neonatal hypothyroidism, breast-feeding is contraindicated in the presence of this drug.
Pediatric use]
The safety and efficacy of amiodarone hydrochloride in pediatric patients have not been established, therefore, its use in children is not recommended.
Geriatric use]
A sufficient number of subjects aged ≥ 65 years were not included in clinical studies of amiodarone tablets to determine whether their response to the drug was different from that of younger subjects. Other reported clinical experiences have not found differences in response between older and younger patients. In general, doses given to the elderly should be carefully selected and, in general, should be started at the lower end of the dose range, taking into account their more rapid decompensation of hepatic, renal, or cardiovascular function and concomitant diseases and other drug therapy. See other sections or follow your doctor’s instructions.
Drug Interactions
Anti-arrhythmic drugs
Many antiarrhythmic drugs can inhibit the autoregulation, conduction, and contractility of the heart. Combination of different antiarrhythmic drugs may provide beneficial therapeutic effects, but close clinical and electrocardiographic monitoring is usually required. Combination of antiarrhythmic agents that can induce torsional ventricular tachycardia (propyzamide, quinidine, sotalol, etc.) is strictly prohibited.
Combination of antiarrhythmic drugs of the same class is not recommended except in certain exceptional cases, as it increases the risk of adverse cardiac effects.
Combination of drugs with negative inotropic, heart rate slowing and/or atrioventricular conduction effects requires close clinical and electrocardiographic monitoring.
Drugs that may cause tip-twisting ventricular tachycardia
There are a number of medications that can cause severe arrhythmias, such as antiarrhythmic drugs and other medications. Hypokalemia is a predisposing factor, as is bradycardia or pre-existing congenital or acquired QT interval prolongation.
Drugs that predispose to tip-twisting ventricular tachycardia include, in particular, class Ia antiarrhythmic drugs, class III antiarrhythmic drugs, and certain psychosuppressive drugs. For erythromycin, spiramycin, and vincristine, only intravenous administration of the drug form causes this interaction.
The combination of two drugs that can cause tip-twisting is usually prohibited. The exceptions are methadone and certain subgroups of drugs.
Antiparasitic drugs (halofantrine, benflunomide, and pentazocine) should not be combined with other drugs that can cause tip-twisting.
Psychostimulants that can induce torsional ventricular tachycardia are also inappropriate, but are not strictly prohibited in combination with other drugs that can cause torsional ventricular tachycardia.
Heart rate slowing drugs
Many drugs can cause bradycardia. Common ones include class Ia antiarrhythmics, beta-blockers, some class III antiarrhythmics, some calcium channel blockers, digitalis, bradykinin, and anticholinesterase agents. Heart rate slowing drugs can lead to an increased risk of ventricular arrhythmias, especially torsional ventricular tachycardia, and should be monitored clinically and by electrocardiogram.
Amiodarone should be used with caution in patients treated with beta-blockers (e.g., propranolol) or calcium channel antagonists (e.g., verapamil, diltiazem)
because of the possibility of bradycardia, sinus arrest, and AV block; in patients with severe bradycardia or sinus arrest, amiodarone may be continued after pacemaker implantation, if necessary.
Drugs to prolong the QT interval
Because the risk of tip-twisting ventricular tachycardia may be increased (see Precautions), the combination of amiodarone with drugs known to prolong the QT interval should be based on a careful assessment of the potential risks and benefits for each patient and testing of the patient for QT prolongation.
Fluoroquinolones, macrolide antibiotics, and pyrroles are known to cause QTc prolongation. QTc prolongation, with or without TdP, has been reported in patients on amiodarone when concomitantly given fluoroquinolones, macrolide antibiotics, and pyrroles.
Propiamine promotes QT interval prolongation and may cause arrhythmias.
Surgery and general anesthesia
Potentially serious complications have been reported in patients undergoing general anesthesia: bradycardia (unresponsive to atropine), hypotension, conduction block, and reduced cardiac output.
Serious respiratory complications have also been reported, usually immediately after surgical treatment (acute respiratory distress syndrome in adults), which are very rare and sometimes fatal; they may be related to high oxygen interactions.
Contraindicated combination medications
Drugs that predispose to tip-twisting ventricular tachycardia.
Class Ia antiarrhythmic drugs (quinidine, hydroquinidine, propiamine).
Class III antiarrhythmic drugs (dofetilide, ibritilide, sotalol).
other drugs such as bendipride, cisapride, diphenhydramine, erythromycin (intravenous administration), imipramine, vincristine (intravenous administration), moxifloxacin, spiramycin (intravenous administration)
Sutropil: increased risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia.
Not recommended combination drugs
Cyclosporine
Increased circulating levels of cyclosporine due to attenuated metabolism of cyclosporine in the liver, and risk of nephrotoxicity.
During and after the application of amiodarone therapy, the blood concentration of cyclosporine needs to be analyzed and the renal function needs to be compared, and the administered dose needs to be adjusted.
Verapamil for injection
There is a risk of bradycardia and atrioventricular block.
If such coadministration is unavoidable, close clinical monitoring and continuous ECG monitoring must be implemented.
Diltiazem for injection
There is a risk of bradycardia and atrioventricular block. If this combination is unavoidable, then close clinical monitoring and continuous ECG monitoring are required.
Halofantrine, pentamidine, phenformin
Increased risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia. If possible, discontinue non-anti-infective drugs that induce tip-twisting ventricular tachycardia. If this combination is unavoidable, it is necessary to compare QT intervals beforehand and to perform ECG monitoring of the patient.
Psychosuppressive drugs that predispose to tip-twisting ventricular tachycardia.
Phenothiazine psychosuppressive drugs (chlorpromazine, cyromazine, levomepromazine, thioridazine, trifluoperazine), acylbenzenes (amisulpride, sulpiride, tebrile, verapride), butylphenols (haloperidol, haloperidol) and other psychosuppressive drugs (pimozide).
Increased risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia.
Methadone
Increases the risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia.
Fluoroquinolone should be avoided while the patient is taking amiodarone. Combinations requiring prophylaxis
Amiodarone and/or its metabolites (desethylamiodarone) inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6 and P-glycoprotein and may increase their substrate exposure. Due to the long half-life of amiodarone, its effects may still be observed months after discontinuation of amiodarone.
Since amiodarone is a CYP3A4 and CYP2C8 substrate, CYP3A4 inhibitors and CYP2C8 inhibitors may have the potential to inhibit amiodarone metabolism thereby increasing amiodarone exposure. Patients treated with amiodarone are advised to avoid exposure to CYP3A4 inhibitors (e.g. grapefruit juice and certain pharmaceutical products).
CYP2C9 substrates
Amiodarone can increase the concentration of CYP2C9 substrates such as warfarin or phenytoin by inhibiting cytochrome P450 2C9.
Warfarin
The combination of warfarin and amiodarone can increase the plasma concentration of anticoagulant drugs and increase the effect of anticoagulant drugs, which may lead to severe or fatal bleeding.
More frequent monitoring of prothrombin international normalized ratio (INR) levels and adjustment of the dose of oral anticoagulants are required both during and after termination of amiodarone therapy.
Phenytoin (conclusion inferred from fosphenytoin)
The combination of phenytoin and amiodarone may lead to phenytoin drug overdose, resulting in neurological symptoms.
Once symptoms of drug overdose occur, clinical monitoring should be performed immediately and the dose should be reduced to control the blood levels of phenytoin.
CYP2D6 substrates
Flucainide
Amiodarone increases flunica plasma concentrations via cytochrome CYP2D6 inhibition, therefore flunica dosing should be adjusted.
Dextromethorphan is a substrate for CYP2D6 and CYP3A4. Amiodarone has an inhibitory effect on CYP2D6.
CYP 3A4 substrates
Amiodarone is an inhibitor of CYP 3A4, and when these drugs (CYP3A4 substrates) are used with amiodarone, it may result in high plasma concentrations of these drugs and increase their toxicity.
Fentanyl
The coadministration of fentanyl with amiodarone may cause hypotension, bradycardia, and decrease cardiac blood output.
HMG-CoA reductase inhibitors
Statins metabolized via CYP3A4 such as simvastatin, atorvastatin and lovastatin are at increased risk of muscle toxicity when coadministered with amiodarone and may require lower starting and maintenance doses of other CYP3A4 substrates because amiodarone increases plasma concentrations of these drugs.
Simvastatin: Increased risk of adverse effects (dose-dependent) such as rhabdomyolysis (decreased hepatic metabolism of cholesterol-lowering drugs). Simvastatin should not be administered at doses exceeding 20 mg/day.
Lovastatin: In patients taking amiodarone, lovastatin should not be administered at doses greater than 40 mg/day.
At this dose, if the therapeutic goal is not achieved, then other statins without such drug interactions are applied.
When treating with amiodarone, the combination of statins that are not metabolized by CYP3A4 is recommended.
Tacrolimus
Amiodarone may increase the blood level of tacrolimus by inhibiting its metabolism.
The blood concentration of tacrolimus should be measured during the combination and when amiodarone is discontinued, and renal function should be monitored and the dose of tacrolimus should be adjusted.
Immunosuppressants
Reports suggest that when cyclosporine (a substrate of CYP3A4) is combined with oral amiodarone, it may cause a persistent increase in plasma concentrations of cyclosporine in patients despite a reduced dose of cyclosporine, leading to an increase in serum creatinine levels.
Other drugs metabolized by CYP 3A4
Clopidogrel (an inactive thienopyridine precursor drug) is metabolized in the liver by CYP3A4 to active metabolites. A potential interaction between clopidogrel and amiodarone has been reported that may result in ineffective inhibition of platelet aggregation by clopidogrel.
Trazodone (an antidepressant) is primarily metabolized by CYP3A4. Prolonged QT interval and tip-twisting ventricular tachycardia have been reported when trazodone is combined with amiodarone.
Loratadine (a non-sedating histamine H1
antagonist) is primarily metabolized by CYP3A4. Prolonged QT interval and tip-turn ventricular tachycardia have been reported with loratadine in combination with amiodarone.
Lidocaine, tacrolimus, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine, and colchicine.
PgP substrates
Amiodarone is a PgP inhibitor. Combination of this product with PgP substrates will result in increased exposure.
Digitalis analogues
Inhibits autoregulation (excessive bradycardia) and atrioventricular conduction.
In patients treated with digoxin, oral administration of amiodarone can lead to increased serum digoxin concentrations, resulting in clinical toxicity. When amiodarone is combined with digoxin for 1 day, it can increase serum digoxin concentrations by 70%. After initiation of oral amiodarone therapy, the need for digitalis therapy should be carefully evaluated and the dose reduced by approximately 50%, or discontinued. If digitalis therapy is continued, digitalis blood levels should be closely monitored and patients should be observed for clinical signs of digitalis toxicity. These precautions should probably also apply to digitalis toxicity.
Dabigatran.
The combination of amiodarone with dabigatran should be used with caution because of its increased risk of bleeding. Dabigatran dosing may need to be reduced if necessary according to the instructions.
CYP3A4 inhibitors
Protease inhibitors.
Protease inhibitors are known to inhibit CYP3A4 to varying degrees. in one case report, amiodarone concentrations increased from 0.9 mg/L to 1.3 mg/L in a patient taking amiodarone 200 mg and indinavir 800 mg three times daily. desethylamiodarone (DEA) concentrations were not affected and there were no signs of toxicity. Monitoring for amiodarone toxicity should be considered during combined protease inhibitor therapy with serial measurements of amiodarone serum concentrations.
Cimetidine (histamine H2 antagonist) inhibits CYP3A4 and can increase serum amiodarone levels.
Administration of grapefruit juice to healthy volunteers increased the AUC of amiodarone by 50%, increased Cmax by 84%, and decreased DEA to non-quantifiable concentrations. Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased amiodarone plasma levels; therefore, patients should not use grapefruit juice during oral amiodarone administration.
CYP3A4 inducers
Some drugs are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme inducers), resulting in lower serum amiodarone concentrations and thus reducing the efficacy of amiodarone.
Rifampin is a potent CYP3A4 inducer. It has been reported that taking rifampin along with oral amiodarone can lead to lower serum concentrations of amiodarone and desethylamiodarone.
St. John’s wort (i.e., Hypericum) induces CYP3A4. Given that amiodarone is a CYP3A4 substrate, concomitant use of St. John’s wort in patients treated with amiodarone may result in decreased amiodarone levels in patients.
Calaisenamide promotes hepatic and intestinal digestion of amiodarone, thereby reducing serum concentrations of amiodarone and t½.
Beta-blockers other than sotalol (contraindicated in combination) (including esmolol)
Systolic, autoregulatory and conduction abnormalities (inhibition of compensatory sympathetic mechanisms) Requires implementation of ECG and clinical monitoring.
Combination with beta-blockers (bisoprolol, carvedilol, metoprolol, nebivolol) in patients with heart failure
Affects the risk of autoregulation and cardiac conduction disturbances (synergistic effect) with excessive bradycardia
Increased risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia, requiring regular clinical and electrocardiographic monitoring
Oral diltiazem
Risk of bradycardia and atrioventricular block, especially in elderly patients. Clinical monitoring and ECG monitoring need to be implemented.
Certain macrolides (azithromycin, clarithromycin, roxithromycin)
Increase the risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia.
ECG and ECG monitoring are required during drug administration.
Oral verapamil
Risk of bradycardia and atrioventricular block, especially in elderly patients. Clinical monitoring and ECG monitoring need to be performed.
Drugs that cause hypokalemia: potassium-removing diuretics (single or combination), stimulant laxatives, amphotericin B (intravenous administration), glucocorticoids (systemic administration), ticlopidine
Increased risk of ventricular arrhythmias, especially tip-twisting ventricular tachycardia (hypokalemia is a contributing factor). ECG, laboratory tests and clinical signs should be monitored.
Hypokalemia must be prevented (and corrected); the QT interval should be monitored, and antiarrhythmic drugs should not be used if “torsional ventricular tachycardia” occurs (ventricular pacing should be initiated; magnesium should be administered by the intravenous route).
Lidocaine
Because amiodarone decreases hepatic metabolism of lidocaine, it increases the risk of lidocaine plasma concentrations when combined with lidocaine, which may have adverse neurological and cardiac effects.
Clinical and ECG monitoring should be available and, if necessary, lidocaine plasma concentrations should be tested. If necessary, adjust the therapeutic dose of lidocaine during and after discontinuation of amiodarone therapy.
During local anesthesia, oral amiodarone and lidocaine (CYP3A4 substrate) cause sinus bradycardia. With increasing concentrations of lidocaine, co-administration of intravenous amiodarone can lead to seizures.
Orlistat
Has a risk of decreasing plasma concentrations of amiodarone and its active metabolites.
Perform clinical monitoring, and ECG if necessary.
Emphasize combination with the following drugs
Drugs causing bradycardia: calcium channel blockers (verapamil) with bradycardic effect, beta-blockers (except sotalol, as the combination is contraindicated), colistin, chlorpheniramine, digitalis, hexafluoro-piperaquine, anticholinesterase drugs (donepezil, galantamine, carbaplatin, tacrine, ampicillin, pyridostigmine, neostigmine), pilocarpine
Risk of severe bradycardia (cumulative effect)
Long-term oral administration of amiodarone (> 2 weeks) will weaken the metabolism of sodium toluenes, dextromethorphan and methotrexate.
[Drug overdose].
Acute administration of large doses of amiodarone is poorly documented in the literature. Some cases of sinus bradycardia, ventricular arrhythmias (especially tip-twisting ventricular arrhythmias) and impaired liver function have been reported. Symptomatic treatment must be given. In addition to general supportive measures, the patient’s heart rhythm and blood pressure should be monitored, and if accompanied by bradycardia, beta-adrenergic agonists or a pacemaker may be used. If hypotension is accompanied by inadequate tissue perfusion, positive inotropic and/or vasopressant agents should be used. Amiodarone and its metabolites are non-dialysable.
The acute oral LD50 of amiodarone hydrochloride in mice and rats is >3,000 mg/kg.
Pharmacology and Toxicology
Pharmacological properties
Anti-arrhythmic properties.
Prolongation of the phase 3 action potential time course in cardiac cells, caused by inhibition of potassium channels (Vaughan Williams class III).
Causes a bradycardic effect by decreasing the autoregulation of the sinus node. This effect cannot be antagonized by atropine.
Non-competitive anti-alpha and beta anti-adrenergic effects.
slowing of sinus, atrial and AV node conduction, an effect that becomes more pronounced the faster the heart rate.
No change in ventricular conduction.
a prolongation of the atrial, AV node and ventricular level of the expiration period and a decrease in myocardial excitability
slowing of atrioventricular collateral conduction and lengthening of the expiration period.
Other characteristics.
A decrease in oxygen consumption due to a moderate decrease in peripheral resistance and a slowing of the heart rate.
Increased coronary blood flow due to direct action on the smooth muscle of small myocardial arteries, lower peripheral resistance and blood pressure, and maintenance of cardiac output without negative inotropic effects.
A meta-analysis of 13 controlled, randomized, prospective studies, which included 6553 patients with recent myocardial infarction (78%) and chronic heart failure (22%), was presented.
Patients were followed up for a mean of 0.4-2.5 years. The mean daily maintenance dose ranged from 200-400 mg.
This meta-analysis showed a 13% reduction in overall mortality (CI95% 0.78-0.99; p = 0.030) and a 29% reduction in rhythm-related mortality (CI95% 0.59-0.85; p = 0.0003) in patients treated with amiodarone.
However, given the heterogeneity of these studies, including differences in relevant population selection, duration of follow-up, methodologies used, and outcome analysis, the results of the studies need to be interpreted with caution. The rate of withdrawal was higher in the amiodarone treatment group (41%) than in the placebo treatment group (27%).
Hypothyroidism developed in 7% of patients treated with amiodarone compared to 1% of patients in the placebo group. Hyperthyroidism was diagnosed in 1.4% of patients treated with amiodarone compared to 0.5% of patients in the placebo group.
Interstitial lung disease developed in 1.6% of patients treated with amiodarone compared to 0.5% of patients in the placebo-treated group.
[Pharmacokinetics].
Amiodarone is a slow-transporting drug with high tissue affinity.
The oral bioavailability of the drug varies from individual to individual and ranges from 30%-80% (mean value 50%). Peak plasma concentrations were reached after 3-7 hours of a single dose. Therapeutic activity was obtained on average within 1 week (a few days to two weeks).
Amiodarone has a long half-life with high inter-individual variability (20-100 days). On the 1st day of treatment, the drug accumulates in most of the body’s tissues, especially in adipose tissue. After a few days, clearance of the drug begins, and after several months, the intake/exhaustion reaches equilibrium, the exact time required for equilibrium being dependent on the individual.
These characteristics explain the purpose of loading dose application, in order to quickly reach tissue saturation levels for therapeutic efficacy.
Amiodarone is metabolized by CYP450 enzymes (specifically CYP3A4 and CYP2C8) to desethylamiodarone (DEA). CYP3A4 isoenzymes are found in the liver and intestine.
Amiodarone is mainly cleared by hepatic metabolism and biliary excretion, and trace amounts of amiodarone or DEA can be found in the urine.
Neither amiodarone nor DEA is dialyzable.
Part of the iodine is dissociated from the drug and appears as iodide in the urine; this corresponds to 6 mg of the 200 mg daily dose of amiodarone administered over a 24-hour period. the rest of the drug (the largest fraction of iodine) is excreted in the stool after passing through the liver.
The negligible urinary excretion means that the drug can be applied at usual doses in patients with impaired renal function.
The placental transport of amiodarone and its metabolites is limited and is about 10-50%. Both the maternal drug and its metabolites are detectable in breast milk.
Amiodarone has a high protein binding rate (approximately 96%).
Clearance of the drug continues for several months after cessation of treatment. The residual activity of the drug can last from 10 days to 1 month, which should be noted.
Storage】Store under shade and seal.
Package】Polyvinyl chloride solid pharmaceutical hard tablets and pharmaceutical aluminum foil. 9 tablets/plate×1 plate/box, 9 tablets/plate×2 plate/box, 12 tablets/plate×1 plate/box, 12 tablets/plate×2 plate/box, 15 tablets/plate×1 plate/box, 15 tablets/plate×2 plate/box.
【Validity】24 months
【Execution standard
【Approval number】State Drug Certificate H37021456
[Drug marketing license holder
Name: Shandong Xinyi Pharmaceutical Co.
Address: No.1 Xingping Road, Plain County
Zip code: 253100
Telephone: 0534-2160269
Fax number: 0534-2160268
Web address: www.sd-sinepharm.com
【Manufacturing enterprise】.
Company name: Shandong Xinyi Pharmaceutical Co.
Production Address: No.1 Xingping Road, Pingping County
Postal Code: 253100
Telephone: 0534-2160269
Fax number: 0534-2160268
Web address: www.sd-sinepharm.com