Amiodorone Inj 150mg/3ml-Sanofi


UGX19,500

Cordarone IV (amiodarone hydrochloride) Intravenous is an antiarrhythmic drug used to treat and prevent frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy. Cordarone I.V. also can be used to treat patients with VT/VF for whom oral Cordarone is indicated, but who are unable to take oral medication. The brand name Cordarone IV is discontinued, but generic versions may be available. Common side effects of Cordarone IV (amiodarone hydrochloride) include:

  • low blood pressure (hypotension),
  • slow heart rate,
  • cardiac arrest,
  • nausea,
  • fever,
  • congestive heart failure,
  • abnormal heart rhythm,
  • cardiogenic shock, and
  • liver function test abnormalities.

The recommended starting dose of Cordarone I.V. is about 1000 mg over the first 24 hours of therapy. Cordarone IV may interact with protease inhibitors, loratadine, cimetidine, antidepressants, grapefruit juice, cyclosporine, simvastatin, digoxin, other antiarrhythmic drugs, beta-blockers, calcium channel antagonists, anticoagulants, clopidogrel, antibiotics, St. Johns Wort, fentanyl, lidocaine, dextromethorphan, cholestyramine, disopyramide, azole antifungals, propranolol, diltiazem, verapamil, phenytoin, dextromethorphan, methotrexate, and diuretics. Tell your doctor all medications and supplements you use. Cordarone IV may be harmful to a fetus if administered during pregnancy. Tell your doctor if you are pregnant or plan to become pregnant before using Cordarone IV. This drug passes into breast milk. Breastfeeding while using this drug is not recommended.

Our Cordarone IV (amiodarone hydrochloride) Intravenous Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

SIDE EFFECTS

In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received Cordarone I.V. for at least 1 week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days.

The most important treatment-emergent adverse effects were hypotension, asystole/cardiac arrest/electromechanical dissociation (EMD), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse effects. The most common adverse effects leading to discontinuation of Cordarone I.V. therapy were hypotension (1.6%), asystole/cardiac arrest/EMD (1.2%), VT (1.1%), and cardiogenic shock (1%).

The following table lists the most common (incidence 2%) treatment-emergent adverse events during Cordarone I.V. therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse events appeared to be dose-related.

Other treatment-emergent possibly drug-related adverse events reported in less than 2% of patients receiving Cordarone I.V. in Wyeth-Ayerst controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting.

Postmarketing Reports

In postmarketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, renal impairment, renal insufficiency, acute renal failure, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pleuritis, pseudotumor cerebri, syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, hallucination, confusional state, disorientation, delirium, epididymitis, and impotence also have been reported with amiodarone therapy.

Also, in patients receiving recommended dosages of Cordarone I.V., there have been postmarketing reports of the following injection site reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing (see DOSAGE AND ADMINISTRATION).

DRUG INTERACTIONS

Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, chiefly with the oral formulation, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, the potential for drug interactions exists not only with concomitant medication but also with drugs administered after discontinuation of amiodarone.

Antiarrhythmics: Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have been used concurrently with amiodarone. There have been case reports of increased steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of flecainide have been reported to increase in the presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these drugs are administered concomitantly. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring. A combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During the transfer to oral amiodarone, the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of oral amiodarone (see DOSAGE AND ADMINISTRATION, Intravenous to Oral Transition). The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose.

Antihypertensives: Amiodarone should be used with caution in patients receiving β-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest.

Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely. A similar effect has been reported with fluindione, an oral vitamin K antagonist when administered concomitantly with Cordarone.

Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and Cordarone resulting in ineffective inhibition of platelet aggregation has been reported.

Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and a potential decrease in efficacy. Reported examples of this interaction include the following:

Antibiotics

Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone.

Other substances, including herbal preparations

St. Johns Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. Johns Wort in patients receiving amiodarone could result in reduced amiodarone levels.

Other reported interactions with amiodarone

Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.

Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone.

Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6.

Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t½.

Disopyramide increases QT prolongation which could cause arrhythmia.

Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See PRECAUTIONS, Proarrhythmia.)

Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil.

Volatile Anesthetic Agents: (

In addition to the interactions noted above, chronic (> 2 weeks) oral Cordarone administration impairs the metabolism of phenytoin, dextromethorphan, and methotrexate.

Electrolyte Disturbances

Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being treated with Cordarone I.V., as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.

WARNINGS

Hypotension

Hypotension is the most common adverse effect seen with Cordarone I.V. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with Cordarone I.V. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose-related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in Cordarone I.V. therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients.

Hypotension should be treated initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. In some cases, hypotension may be refractory resulting in the fatal outcomes

Bradycardia and AV Block

Drug-related bradycardia occurred in 90 (4.9%) of 1836 patients in clinical trials while they were receiving Cordarone I.V. for life-threatening VT/VF; it was not dose-related. Bradycardia should be treated by slowing the infusion rate or discontinuing Cordarone I.V. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Patients with a known predisposition to bradycardia or AV block should be treated with Cordarone I.V. in a setting where a temporary pacemaker is available.

Liver Enzyme Elevations

Elevations of blood hepatic enzyme valuesalanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)are seen commonly in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients who have had a recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. Approximately 54% of patients receiving Cordarone I.V. in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment.

Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of Cordarone I.V. at a much higher loading dose concentration and much faster rate of infusion than recommended in Dosage and Administration. In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of Cordarone I.V. therapy, but patients receiving Cordarone I.V. should be monitored carefully for evidence of progressive hepatic injury. Consideration should be given to reducing the rate of administration or withdrawing Cordarone I.V. in such cases.

Proarrhythmia

Like all antiarrhythmic agents, Cordarone I.V. may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation by Cordarone I.V. of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving Cordarone I.V., torsade de pointes or new-onset VF occurred infrequently (less than 2%). Patients should be monitored for QTc prolongation during infusion with Cordarone I.V. Combination of amiodarone with other antiarrhythmic therapy that prolongs the QTc should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent.

Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. 

The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient.

A careful assessment of the potential risks and benefits of administering Cordarone I.V. must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia, which may result in death, in these patients.

Pulmonary Disorders

Early-onset pulmonary toxicity

There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with Cordarone I.V. Findings have included pulmonary infiltrates and/or mass on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death.

ARDS

Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. ARDS is a disorder characterized by bilateral, diffuse pulmonary infiltrates with pulmonary edema and varying degrees of respiratory insufficiency. The clinical and radiographic picture can arise after a variety of lung injuries, such as those resulting from trauma, shock, prolonged cardiopulmonary resuscitation, and aspiration pneumonia, conditions present in many of the patients enrolled in the clinical studies. There have been postmarketing reports of ARDS in Cordarone I.V. patients. Cordarone I.V. may play a role in causing or exacerbating pulmonary disorders in those patients.

Postoperatively, occurrences of ARDS have been reported in patients receiving oral Cordarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on Cordarone.

Pulmonary fibrosis

Only 1 of more than 1000 patients treated with Cordarone I.V. in clinical studies developed pulmonary fibrosis. In that patient, the condition was diagnosed 3 months after treatment with Cordarone I.V., during which time she received oral Cordarone. Pulmonary toxicity is a well-recognized complication of long-term Cordarone use (see labeling for oral Cordarone).

Loss of Vision

Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. In some cases, visual impairment has progressed to permanent blindness. Amiodarone I.V. is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy and can also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, the prompt ophthalmic examination is recommended. The appearance of optic neuropathy and/or neuritis calls for a re-evaluation of amiodarone therapy. The risks and complications of antiarrhythmic therapy with amiodarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including fundoscopy and slit-lamp examination, is recommended during the administrations of amiodarone.

Long-Term Use

See labeling for oral Cordarone. There has been limited experience in patients receiving Cordarone I.V. for longer than 3 weeks.

Thyrotoxicosis

Cordarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED (see PRECAUTIONS, Thyroid Abnormalities).

Neonatal Hypo- or Hyperthyroidism

Although Cordarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with its oral administration. If Cordarone I.V. is administered during pregnancy, the patient should be apprised of the potential hazard to the fetus.

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