Amiodarone HCI Rythma Cute Aa) IE Solution for Intravenous Infusion Antiarrhythmic FORMULATION Each mL solution for intravenous (IV) infusion contains: Amiodarone Hydrochloride. 50 mg PRODUCT DESCRIPTION Amiodarone HCI (Rythma®) 50 mg/mL. Solution for Intravenous Infusion - Clear solution, colorless to yellowish, sterile liquid packaged in a 5 mL sterile ampule PHARMACODYNAMICS Amiodarone is both an antiarrhythmic and a potent vasodilator. Amiodarone is considered a “broad spectrum” antiarrhythmic with multiple and complex electrophysiological effects. Although its exact mechanism of action is not completely known, amiodarone is considered a class Ill compound using the traditional Vaughan-Williams classification scheme for antiarrhythmic compounds. Like the other class III antiarrhythmics, bretylium and sotalol, amiodarone acts directly on the myocardium to delay repolarization and increase the duration of the action potential. Delayed repolarization is a result of inhibition of potassium ion fluxes that normally occur during phase 2 and 3 of the action potential. This results in prolongation of the effective refractory period in all cardiac tissue (eg., atria, ventricles, AV node, and His-Purkinje system). Amiodarone exerts this antifibrilatory effect without significantly altering the myocardial membrane potential. By definition, class Ill agents act only on the repolarization phase of the action potential and therefore should leave conduction unchanged. However, amiodarone has also been shown to inhibit the inward sodium currents which is a use-dependent class | activity. The result of this cellular action is a slowing of the upstroke velocity of phase 0 which reduces the rate of membrane depolarization and impulse conduction. Amiodarone also depresses the automaticity of both the SA and AV nodes directly (class II effect), and slows conduction in the His-Purkinje system and in the accessory pathway of patients with Wolff-Parkinson-White syndrome. Amiodarone also noncompetitively inhibits alpha- and beta-receptors, and possesses both vagolytic and calcium-channel blocking properties. The drug relaxes both smooth and cardiac muscles, causing decreases in coronary and peripheral vascular resistance, left ventricular end-diastolic pressure (LVEDP) and systolic blood pressure, thereby decreasing afterload PHARMACOKINETICS After intravenous administration, amiodarone is rapidly and widely distributed. Peak serum concentrations after single 5 mg/kg 15-minute intravenous infusions in healthy subjects range between 5 and 41 mg/L. Peak concentrations after 10-minute infusions of 150 mg Amiodarone Hydrochloride injection in patients with ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT) range between 7 and 26 mg/L. Due to rapid distribution, serum concentrations decline to 10% of peak values within 30 to 45 minutes after the end of the infusion, In vitro, amiodarone is approximately 96% bound to plasma proteins, mainly to albumin and to a lesser extent, to a high density lipoprotein that is probably lipoprotein. Amiodarone is metabolized to N-desethyl amiodarone (DEA) 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 and possibly, DEA, cross the placenta to a limited extent. In pregnant women receiving amiodarone, ratios of umbilical venous to maternal venous plasma concentrations of amiodarone and DEA were 0.1 - 0.28 and 0.25 - 0.55, respectively. Amiodarone and DEA are distributed into milk in concentrations substantially higher than concurrent maternal plasma concentrations. Limited data in a breastfeeding woman indicate amiodarone and DEA milk-to-plasma ratios ranging from 2.3 - 9.1 and 0.8 - 3.8, respectively. Amiodarone's elimination is primarily by hepatic metabolism and biliary excretion. Amiodarone or DEA excretion in the urine is negligible, Neither amiodarone nor DEA is dialyzable. After IV administration in healthy individuals, amiodarone's total plasma clearance averages approximately 1.9mL/minute per kg. Although not clearly established, total apparent plasma clearance of the drug appears to decrease with time. Factors of age, gender, and renal or hepatic disease appear to have no effect on the disposition of amiodarone or DEA. INDICATIONS + Treatment of severe rhythm disorders, especially the following - Supraventricular rhythm disorders - Tachycardia associated with Wolff-Parkinson-White syndrome. - Ventricular rhythm disorder - Recurrent ventricular fibrillation (VF) - Recurrent hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy + Treatment of patients with rhythm disorders where a rapid response is required or where oral administration is not possible DOSAGE AND ADMINISTRATION + Amiodarone should only be used in a special care unit with continuous monitoring of blood pressure and ECG. It should be administered only by physicians who are experienced in the treatment of fatal arrhythmias and are totally familiar with the risks and benefits of amiodarone therapy. + Carefully adjust dosage according to individual requirements and response, patient tolerance, and the patient's general condition and cardiovascular status. + The recommended IV Amiodarone HCI starting dose over the first 24 hours is approximately 4000 mg, administered by the infusion regimen below. (See Table 1) Table 1. Amiodarone IV Infusion Dosing and Dilution Instructions (First 24-Hours Infusion Regimen) Three-Phase Dosing and Dilution Instructions Infusion Sequence Administration Initial 450 mg (3 mL) Dilute 3 mL Amiodarone HC! |.V. Rapid over 10 minutes | (150 mg) with 100 mL Dextrose 5% Infusion Rate: 15 mg/min_ | (D:W), resulting in a final concentration Loading | Phase of 1.5 mg/mL. Infusion. ->——— a —| ‘Slow 360 mg Dilute 18 mL Amiodarone HCI LV. Infusion over 6 hours (900 mg) with 500 mL DsW to a final Phase Rate: 1 mg/min concentration of 1.8 mg/mL Maintenance 540 mg Reduce slow loading infusion rate over 18 hours Infusion Rate: 0.5 mgimin | 120.5 mglmin * After the first 24 hours, continue a maintenance infusion rate of 0.5 mg/min (j.e., 720 mg over 24 hours). + In the event of breakthrough episodes of ventricular fibrillation or hemodynamically unstable ventricular tachycardia, supplemental amiodarone hydrochloride infusions of 150 mg administered over 10 minutes at a rate of 15 mg/minute may be given * Clinical trials on IV Amiodarone HCI reported that a maintenance infusion of up to 0.5 mg/minute can be administered with caution for 2-3 weeks, regardless of patient's age, renal function or left ventricular function. There has been limited experience on the use of IV Amiodarone HCI for longer than 3 weeks. Administration + IV Amiodarone should never be administered via a peripheral vein. It should always be administered exclusively as an infusion through a central venous catheter. Injection via the peripheral venous route, even at a very slow rate can cause local effects such as superficial phlebitis, and may aggravate hypotension, heart failure, myocardiopathy, or severe respiratory insufficiency. * For infusions lasting >1 hour, the concentration should not exceed 2 mg/mL unless administered via a central venous catheter. Infusions lasting >2 hours must be administered in polyolefin or glass bottles containing D:W. Use of evacuated glass containers for admixing amiodarone is not recommended as incompatibility with a buffer in the container may cause precipitation. * Amiodarone injection should only be administered using a volumetric infusion pump. An in-line filter should be used during administration. * Polyvinyl chloride (PVC) tubing should be used during IV administration. The recommended dosing regimens have taken into account the amount of amiodarone adsorbed to PVC tubing Admixture Incompatibilit Amiodarone IV in D-W, in a concentration of 4 mg/mL, is incompatible and forms a precipitate with the following drugs: Aminophyliine, cefamandole, cefazolin, mezlocillin. A concentration of 3 mg ImL Amiodarone IV in D:W forms a precipitate with sodium bicarbonate. Amiodarone is likewise incompatible with heparin. Conversion from IV to Oral Dosage Use IV amiodarone for acute treatment until the patient's ventricular arrhythmias are stabilized. Patients whose arrhythmias have been successfully controlled with IV Amiodarone may be transferred to oral therapy. The optimal dose for changing from IV to oral administration will depend on the IV dose already administered, as well as the bioavailability of oral amiodarone When changing to oral therapy, clinical monitoring is recommended, particularly for elderly patients. Table 2 below provides suggested doses of oral amiodarone to be initiated after varying durations of IV administration. These recommendations are made on the basis of a comparable total body amount of amiodarone delivered by the IV and oral routes, based on 50% bioavailability of oral amiodarone. Table 2. Recommended Oral Amiodarone Dose After IV Infusion Duration of amiodarone IV infusions * Initial daily dose of oral amiodarone <1 week 800 to 1600 mg 1 to 3 weeks 600 to 800 mg > 3 weeks ** 400 mg * Assuming a 720 mg/day infusion (0.5 mg/min) ** Amiodarone IV is not intended for maintenance therapy beyond 3 weeks Stability Amiodarone adsorbs to polyvinyl chloride (PVC) tubing, and the clinical trial dose administration schedule was designed to account for this adsorption. Clinical trials were conducted using PVC tubing; therefore its use is recommended. Amiodarone has been found to leach out plasticizers, including di-ethylhexyl phthalate (DEHP) from IV tubing (including PVC tubing). The degree of leaching increases when infusing amiodarone IV at higher concentrations and lower flow rates than recommended. CONTRAINDICATIONS + Sinus bradycardia and sino-atrial heart block * Sick sinus syndrome or sinus node disease (except when amiodarone is used in conjunction with a pacemaker) * Atrioventricular heart block, bi- or trifascicular conduction disorders, when not used in conjunction with a pacemaker. In such circumstances, amiodarone IV may be used in a special care unit and institute electrosystolic pacing + Evidence or history of thyroid dysfunction. Thyroid function tests should be performed in all patients prior to amiodarone therapy + Combination of amiodarone with drugs which may induce torsades de pointes (see Drug Interactions) + Circulatory collapse, severe arterial hypotension + Known hypersensitivity to amiodarone or to iodine, or to any of the excipients. + Pregnancy, except in exceptional circumstances; breastfeeding women (see Use in Pregnancy and Lactation) WARNINGS AND PRECAUTIONS + Amiodarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity, the most important of which is pulmonary toxicity (i.e., hypersensitivity pneumonitis or interstitial/alveolar pneumonitis). Mild liver injury is likewise common as evidenced by abnormal liver enzymes. Overt liver disease can occur and has been fatal in a few cases. (See Adverse Effects) + Hospitalize patients with indicated arrhythmias while amiodarone loading dose is being given. + Hypotension occurring with IV amiodarone therapy 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. * The pharmacological action of amiodarone includes ECG changes: QT prolongation (related to prolonged repolarization) with the possible development of U-waves; these changes do not reflect toxicity. * In the elderly, heart rate may decrease markedly. * Treatment should be discontinued in case of onset of 2” and 3" degree A-V block, sinoatrial block, or bifascicular block + Amiodarone contains iodine and thus may interfere with radioiodine uptake. However, thyroid function tests T3, T4, ultrasensitive TSH (usTSH) remain interpretable + Dyspnea or non-productive cough may be related to pulmonary toxicity. * Before treatment initiation, perform an ECG, usTSH assay and serum potassium measurement, * Undesirable effects are usually dose-related; therefore, careful attention should be paid to determine the minimum effective maintenance dose in order to avoid or minimize undesirable effects. * Patients should be instructed to avoid exposure to sun or to use protective measures during therapy since amiodarone may induce photosensitization + Amiodarone may induce thyroid disorders particularly in patients with personal or family history of thyroid disorders. Therefore, clinical and biological monitoring is recommended before starting treatment, during treatment and for several months after treatment discontinuation. Serum usTSH level should be measured when regular dysfunction is suspected. DRUG INTERACTIONS Drugs / Food / Dietary or Herbal Supplements Affecting Microsomal Enzymes - Amiodarone is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally the isoenzymes CYP3A4 and CYP2C8. Amiodarone also inhibits CYP2D8, CYP1A2, CYP2C3, and CYP3A4 isoenzymes. Inhibition of these isoenzymes by amiodarone may result in unexpectedly high plasma concentrations of other drugs which are metabolized by these isoenzymes. + HIV Protease inhibitors: HIV protease inhibitors (e.g., ritonavir, amprenavir, indinavir) are known to inhibit CYP3A4 to varying degrees. Monitor for amiodarone toxicity and do serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy. * Loratadine, a non-sedating antihistamine, is metabolized primarily by CYP3A4. QT interval prolongation and torsades de pointes have been reported with the co-administration of loratadine and amiodarone. * Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels. + Trazodone, an antidepressant, is metabolized primarily by CYP3A4, QT interval prolongation and torsades de pointes have been reported with the co-administration of trazodone and amiodarone. * Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine + HMG-CoA reductase inhibitors: Statins (CYP3A4 substrate) in combination with amiodarone have been associated with reports of myopathy/thabdomyolysis. * Antihypertensives: Amiodarone should be used with caution in patients receiving B-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 Amiodarone. * Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and Amiodarone resulting in ineffective inhibition of platelet aggregation has been reported. * Antibiotics: Rifampin is a potent inducer of CYP3A4, Administration of rifampin concomitantly with amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone + Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output. + Lidocaine (CYP3A4 substrate) has been reported to cause sinus bradycardia when given in combination with amiodarone. 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 with resulting impairment in metabolism. * St. John's Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving amiodarone could result in reduced amiodarone levels. * Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased desethylamiodarone (DEA) to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased amiodarone plasma levels; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone Drugs Affecting the QT Interval- Amiodarone prolongs QT. interval. Potentially serious cardiac arthythmias, including torsades de pointes, could occur if amiodarone is administered concomitantly with other drugs that prolong the QT: interval (e.g., cisapride, halofantrine, pimozide, disopyramide, flouroquinolones, macrolide antibiotics, azole antifungal agents) Cardiac glycoside (Digoxin)- Amiodarone given concomitantly with digoxin increases serum digoxin concentration by 70% after one day. On initiation of amiodarone, review the need for digitalis therapy and reduce the dose by ~50% or discontinue digoxin. Closely monitor serum digoxin levels and observe patients for clinical evidence of toxicity, These precautions should be applied to digitoxin as well Antiarrhythmics- Concomitant use of amiodarone with other antiarrhythmic agents (eg., disopyramide, mexiletine, propafenone, flecainide, procainamide, quinidine, bepridil, sotalol, diphemanil) generally should be reserved for patients with life-threatening arrhythmias who do not respond completely to either a single antiathythmic agent or amiodarone alone. When combination therapy with amiodarone is necessary, it is generally recommended that dosage of currently administered antiarrhythmic agent be reduced by 30 - 50% several days after initiation of amiodarone therapy, since the onset of amiodarone's antiarrhythmic effect may be delayed Other reported interactions with amiodarone: + Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t ¥ + Chronic use (>2 weeks) of amiodarone impairs metabolism of phenytoin. Increased hydantoin concentrations with symptoms of toxicity may occur. Also, amiodarone serum levels may be decreased. + Concomitant administration of fentanyl and amiodarone may result in hypotension, bradycardia and decreased cardiac output. + Concomitant administration with non-antiarrhythmic agents including vincamine, sultopride, sparfloxacin, erythromycin IV and pentamidine may cause an increased risk of potentially lethal torsades de pointes. + Coadministration with agents that can produce hypokalemia and/or hypomagnesemia (e.g., potassium-wasting diuretics, amphotericin B, cation exchange resins, stimulant laxatives) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, because of additive arrhythmogenic potential. Any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. + Concomitant use of amiodarone and cyclosporine has produced persistently elevated creatinine despite reduction in dose of cyclosporine + Chronic use (>2 weeks) of amiodarone impairs metabolism of methotrexate Methotrexate toxicity may be increased. + Concomitant administration of amiodarone and rifamycin may cause decreased serum concentrations of amiodarone and its active metabolites, reducing its pharmacologic effect. * Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported. STATEMENT ON USAGE FOR HIGH RISK GROUPS + PREGNANCY AND LACTATION Pregnancy Category D. Amiodarone is contraindicated during pregnancy because there have been reports of neonatal hypo- or hyperthyroidism from amiodarone use. Amiodarone is excreted in breastmilk in significant quantities and is therefore contraindicated in breastfeeding mothers + GERIATRICS In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy + INFANTS AND CHILDREN The safety and effectiveness of amiodarone in children have not been established. UNDESIRABLE EFFECTS The most important adverse effects of IV amiodarone were hypotension, asystole/cardiac arrest/electromechanical dissociation (EMD), cardiogenic shock, CHF, bradycardia, liver function test abnormalities, ventricular tachycardia (VT), and atrioventricular (AV) block Below are the most common treatment-emergent adverse events during IV amiodarone therapy which are considered to be possibly drug-related Body as a whole: Fever Cardiovascular System: Bradycardia, congestive heart failure, heart arrest, hypotension (sometimes fatal), ventricular tachycardia, atrial fibrillation, nodal arrhythmia, prolonged QT interval, shock, sinus bradycardia, ventricular fibrillation, sinus arrest, angioedema Digestive System: Abnormal liver function tests, nausea, abnormal kidney function, diarrhea, increased alanine transaminase (ALT), increased aspartate aminotransferase (AST), vomiting, hepatitis, cirrhosis, pancreatitis Respiratory: Lung edema, respiratory disorder, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pleuritis Gastrointestinal: Nausea, vomiting, constipation, abdominal pain, abnormal salivation, anorexia, epigastric buming or fullness, and pancreatitis Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, exfoliative dermatitis, skin cancer, pruritus, injection site reactions (pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis and skin sloughing) Neurologic: Hallucination, confusional state, disorientation, delirium Hematologic: Thrombocytopenia, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, agranulocytosis Thyroid: Thyroid nodules/thyroid cancer Others: Anaphylactic/anaphylactoid reaction (including shock), renal impairment, renal insufficiency, acute renal failure, pseudotumor cerebri, syndrome of inappropriate antidiuretic hormone secretion (SIADH), vasculitis, granuloma, myopathy, muscle weakness, rhabdomyolysis, epididymitis and impotence OVERDOSE AND TREATMENT There have been reports of some fatal amiodarone overdose. Effects of unintentional IV amiodarone overdose include hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity. Hypotension and cardiogenic shock should be treated by slowing the infusion rate or with standard therapy of vasopressor drugs, inotropic agents, and volume expansion. Bradycardia and AV block may require temporary pacing. Closely monitor hepatic enzyme concentrations. Amiodarone is not dialyzable. CAUTION Foods, Drugs, Devices, and Cosmetics Act prohibits dispensing without prescription. ADVERSE DRUG REACTION REPORTING STATEMENT For suspected adverse drug reaction, seek medical attention immediately and report to the FDA at www.fda.gov.ph and Unilab at (+632)858-1000 or productsafety@unilab.com.ph. By reporting undesirable effects, you can help provide more information on the safety of this medicine. AVAILABILITY Amiodarone HCI (Rythma®) 3mL of S¢mg/mL solution for lV infusion per ampule (Box of 6 ampules) STORE AT TEMPERATURES NOT EXCEEDING 30°C. KEEP OUT OF CHILDREN’S REACH. Date of First Authorization: May 2009 Date of Revision of Package Insert: July 2014 Manufactured by PT Darya-Varia Laboratoria Tbk. Jl. Lanbau Liobaru RT. 007 RW. 009 Kel. Karangasem Barat, Kec. Citeureup Bogor, Jawa Barat — Indonesia Imported and Distributed by UNILAB, Inc. No. 66 United Street, Mandaluyong City Trusted Quality Healthcare_ Metro Manila, Philippines Registration Number: Rythma® 3mL of 50mg/mL solution for IV infusion: DR-XY35608 251602094 Reg. IPOPHIL THE156471IN04