NDC 63629-2076 Amiodarone Hcl

Amiodarone Hydrochloride

NDC Product Code 63629-2076

NDC CODE: 63629-2076

Proprietary Name: Amiodarone Hcl What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Amiodarone Hydrochloride What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used to treat certain types of serious (possibly fatal) irregular heartbeat (such as persistent ventricular fibrillation/tachycardia). It is used to restore normal heart rhythm and maintain a regular, steady heartbeat. Amiodarone is known as an anti-arrhythmic drug. It works by blocking certain electrical signals in the heart that can cause an irregular heartbeat.

Product Characteristics

Color(s):
YELLOW (C48330)
Shape: ROUND (C48348)
Size(s):
7 MM
Imprint(s):
AS;100
Score: 1

NDC Code Structure

  • 63629 - Bryant Ranch Prepack

NDC 63629-2076-1

Package Description: 30 TABLET in 1 BOTTLE

NDC Product Information

Amiodarone Hcl with NDC 63629-2076 is a a human prescription drug product labeled by Bryant Ranch Prepack. The generic name of Amiodarone Hcl is amiodarone hydrochloride. The product's dosage form is tablet and is administered via oral form.

Labeler Name: Bryant Ranch Prepack

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Amiodarone Hcl Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • AMIODARONE HYDROCHLORIDE 100 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POVIDONE, UNSPECIFIED (UNII: FZ989GH94E)
  • D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Cytochrome P450 2C9 Inhibitors - [MoA] (Mechanism of Action)
  • Cytochrome P450 2D6 Inhibitors - [MoA] (Mechanism of Action)
  • Antiarrhythmic - [EPC] (Established Pharmacologic Class)
  • Cytochrome P450 3A4 Inhibitors - [MoA] (Mechanism of Action)
  • P-Glycoprotein Inhibitors - [MoA] (Mechanism of Action)
  • Cytochrome P450 1A2 Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Bryant Ranch Prepack
Labeler Code: 63629
FDA Application Number: ANDA077069 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 01-01-2017 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Amiodarone Hcl Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Pulmonary, Hepatic And Cardiac Toxicity

Amiodarone hydrochloride is intended for use only in patients with the indicated life- threatening arrhythmias because its use is accompanied by substantial toxicity [see Indications and Usage (1)].Amiodarone hydrochloride can cause pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifestdisease at rates as high as 17% in some series of patients. Pulmonary toxicity has been fatal about 10% of the time. Obtain a baselinechest X-ray and pulmonary-function tests, including diffusion capacity, when amiodarone hydrochloride therapy is initiated.Repeat history, physical exam, and chest X-ray every 3 to 6 months [see Warnings and Precautions (5.2)].Amiodarone hydrochloride can cause hepatoxicity, which can be fatal. Obtain baseline and periodic liver transaminases and discontinue or reduce dose if the increase exceeds three times normal, or doubles in a patient with an elevated baseline. Discontinue amiodarone hydrochloride if the patient experiences signsor symptomsof clinical liver injury [see Warnings and Precautions (5.3)].Amiodarone hydrochloride can exacerbate arrhythmias. Initiate amiodarone hydrochloride in a clinical setting where continuous electrocardiogramsand cardiacresuscitation are available [see Warnings and Precautions (5.4)].

1Indications And Usage

Amiodarone hydrochloride is indicated for the treatment of documented, life-threatening recurrent ventricular fibrillation and life-threatening recurrent hemodynamically unstable tachycardia in adults who have not responded to adequate doses of other available antiarrhythmics or when alternative agents cannot be tolerated.

2Dosage And Administration

Dosage must be individualized based on severity of arrhythmia and response. Use the lowest effective dose. Obtain baseline chest x-ray, pulmonary function tests, thyroid function tests, and liver aminotransferases. Correct hypokalemia, hypomagnesemia, and hypocalcemia before initiating treatment.Recommended Dosage:Initiate treatment with a loading doses of 800 to 1600 mg/day until initial therapeutic response occurs (usually 1 to 3 weeks). Once adequate arrhythmia control is achieved, or if side effects become prominent, reduce amiodarone hydrochloride tablets dose to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day.Administration:Administer amiodarone hydrochloride tablets consistently with regard to meals


[see Clinical Pharmacology (12.3)]. Administration of amiodarone hydrochloride tablets in divided doses with meals is suggested for total daily doses of 1000 mg or higher, or when gastrointestinal intolerance occurs.

3Dosage Forms And Strengths

100 mg tablets: yellow colored, round, flat faced beveled edge tablets with “AS” debossed on one side and “100” debossed on the other side.200 mg tablets: yellow colored, round, flat beveled edge tablets with “AS” and “200” debossed on either side of the break line on one side and plain on the other side.400 mg tablets: yellow colored, oval, biconvex tablets with “AS” and “400” debossed on either side of the break line on one side and plain on the other side.

4Contraindications

  • Cardiogenic shock.
  • Sick sinus syndrome, second- or third-degree atrioventricular block, bradycardia leading to syncope without a functioning pacemaker.
  • Known hypersensitivity to the drug or to any of its components, including iodine.

5.1Persistence Of Adverse Effects

Because of the long half-life of amiodarone (15 to 142 days) and its active metabolite desethylamiodarone (14 to 75 days), adverse reactions and drug interactions can persist for several weeks following amiodarone discontinuation


[see Clinical Pharmacology (12.3)].

5.2Pulmonary Toxicity

Amiodarone hydrochloride may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity. Pulmonary toxicity secondary to amiodarone hydrochloride may result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively. Rates of pulmonary toxicity have been reported to be as high as 17% and is fatal in about 10% of cases. Obtain a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, when amiodarone hydrochloride therapy is initiated. Repeat history, physical exam, and chest X-ray every 3 to 6 months or if symptoms occur. Consider alternative antiarrhythmic therapy if the patient experiences signs or symptoms of pulmonary toxicity. Prednisone 40 to 60 mg/day tapered over several weeks may be helpful in treating pulmonary toxicity.Adult Respiratory Distress Syndrome (ARDS)Postoperatively, occurrences of ARDS have been reported in patients receiving amiodarone hydrochloride 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.

5.3Hepatic Injury

Asymptomatic elevations of hepatic enzyme levels are seen frequently, but amiodarone hydrochloride can cause life-threatening hepatic injury. Histology has resembled that of alcoholic hepatitis or cirrhosis. Obtain baseline and periodic liver transaminases. If transaminases exceed three times normal, or doubles in a patient with an elevated baseline, discontinue or reduce dose of amiodarone hydrochloride, obtain follow-up tests and treat appropriately.

5.4Worsened Arrhythmia

Amiodarone hydrochloride can exacerbate the presenting arrhythmia in about 2 to 5% of patients or cause new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (Torsade de Pointes [TdP]).Correct hypokalemia, hypomagnesemia, and hypocalcemia before initiating treatment with amiodarone hydrochloride, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or receiving drugs affecting electrolyte levels, such as diuretics, laxatives, systemic corticosteroids, or amphotericin B.

5.5Visual Impairment And Loss Of Vision

Optic Neuropathy and Optic NeuritisCases of optic neuropathy and optic neuritis, usually resulting in visual impairment and sometimes permanent blindness, have been reported in patients treated with amiodarone and may occur at any time during therapy. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, consider discontinuing amiodarone hydrochloride and promptly refer for ophthalmic examination. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of amiodarone hydrochloride


[see Adverse Reactions (6.1)].


Corneal MicrodepositsCorneal microdeposits appear in the majority of adults treated with amiodarone hydrochloride. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment


[see Adverse Reactions (6.1)].

5.6Thyroid Abnormalities

Amiodarone hydrochloride inhibits peripheral conversion of thyroxine (T


4) to triiodothyronine (T


3) and may cause increased thyroxine levels, decreased T


3 levels, and increased levels of inactive reverse T


3 (rT


3) in clinically euthyroid patients. Amiodarone hydrochloride can cause either hypothyroidism (reported in up to 10% of patients) or hyperthyroidism (occurring in about 2% of patients). Monitor thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction.


Hyperthyroidism may induce arrhythmia breakthrough. If any new signs of arrhythmia appear, the possibility of hyperthyroidism should be considered. Antithyroid drugs, β-adrenergic blockers, temporary corticosteroid therapy may be necessary to treat the symptoms of hyperthyroidism. The action of antithyroid drugs may be delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Amiodarone hydrochloride-induced hyperthyroidism may be followed by a transient period of hypothyroidism.


Hypothyroidism may be primary or subsequent to resolution of preceding amiodarone hydrochloride- induced hyperthyroidism. Severe hypothyroidism and myxedema coma, sometimes fatal, have been reported in association with amiodarone therapy. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the dose of or discontinuing amiodarone hydrochloride and thyroid hormone supplementation.

5.7Bradycardia

Amiodarone hydrochloride causes symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. The risk is increased by electrolytic disorders or use of concomitant antiarrhythmics or negative chronotropes


[see Drug Interactions (7)]. Bradycardia may require a pacemaker for rate control.


Postmarketing cases of symptomatic bradycardia, some requiring pacemaker insertion and at least one fatal, have been reported when ledipasvir/sofosbuvir or sofosbuvir with simeprevir were initiated in patients on amiodarone. Bradycardia generally occurred within hours to days, but in some cases presented up to 2 weeks after initiating antiviral treatment. Bradycardia generally resolved after discontinuation of antiviral treatment. The mechanism for this effect is unknown. Monitor heart rate in patients taking or recently discontinuing amiodarone hydrochloride when starting antiviral treatment


[see Drug Interactions (7)].

5.8Implantable Cardiac Devices

In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillation thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed.

5.9Fetal Toxicity

Amiodarone hydrochloride may cause fetal harm when administered to a pregnant woman. Fetal exposure may increase the potential for cardiac, thyroid, neurodevelopmental, neurological, and growth effects in neonate


[see Use in Specific Populations (8.1)].

5.10Peripheral Neuropathy

Chronic administration of amiodarone hydrochloride may lead to peripheral neuropathy, which may not resolve when amiodarone is discontinued.

5.11Photosensitivity And Skin Discoloration

Amiodarone hydrochloride induces photosensitization in about 10% of patients; some protection may be afforded sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure. Some reversal of discoloration may occur upon drug discontinuation.

5.12Surgery

Volatile Anesthetic AgentsPatients on amiodarone hydrochloride therapy may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.

6Adverse Reactions

  • The following serious adverse reactions are described in more detail in other sections of the prescribing information:Pulmonary Toxicity
  • [see Warnings and Precautions (5.2)]Hepatic Injury
  • [see Warnings and Precautions (5.3)]Worsened Arrhythmia
  • [see Warnings and Precautions (5.4)]Visual Impairment and Loss of Vision
  • [see Warnings and Precautions (5.5)]Thyroid Abnormalities
  • [see Warnings and Precautions (5.6)]Bradycardia
  • [see Warnings and Precautions (5.7)]Peripheral Neuropathy
  • [see Warnings and Precautions (5.10)]Photosensitivity and Skin Discoloration
  • [see Warnings and Precautions (5.11)]

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.At the usual maintenance dose (400 mg/day) and above, amiodarone hydrochloride causes adverse reactions in about three-fourths of all patients, resulting in discontinuation in 7 to 18%.In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with amiodarone hydrochloride, the adverse reactions most frequently requiring discontinuation of amiodarone hydrochloride included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, photosensitivity, blue skin discoloration, hyperthyroidism, and hypothyroidism.The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days):ThyroidCommon: Hypothyroidism, hyperthyroidism.CardiovascularCommon: Congestive heart failure, cardiac arrhythmias, SA node dysfunction. GastrointestinalVery common: Nausea, vomiting.Common: Constipation, anorexia, abdominal pain.DermatologicCommon: Solar dermatitis/photosensitivity.NeurologicCommon: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias, decreased libido, insomnia, headache, sleep disturbances.OphthalmicCommon: Visual disturbances.HepaticCommon: Abnormal liver-function tests, nonspecific hepatic disorders.RespiratoryCommon: Pulmonary inflammation or fibrosis.OtherCommon: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities.Uncommon: Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities.

6.2Postmarketing Experience

The following adverse reactions have been identified during post-approval use of amiodarone hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Hematologic: hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma.


Immune: anaphylactic/anaphylactoid reaction (including shock), angioedema.


Neurologic: pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), demyelinating polyneuropathy.


Psychiatric: hallucination, confusional state, disorientation, delirium.


Cardiac: hypotension (sometimes fatal), sinus arrest.


Respiratory: eosinophilic pneumonia, acute respiratory distress syndrome in the post-operative setting, bronchospasm, bronchiolitis obliterans organizing pneumonia, pulmonary alveolar hemorrhage, pleural effusion, pleuritis.


Gastrointestinal: pancreatitis, acute pancreatitis.


Hepatic: hepatitis, cholestatic hepatitis, cirrhosis.


Skin and Subcutaneous Tissue Disorders: urticaria, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, bullous dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, pruritus, skin cancer, lupus-like syndrome.


Musculoskeletal: myopathy, muscle weakness, rhabdomyolysis.


Renal: renal impairment, renal insufficiency, acute renal failure.


Reproductive: epididymitis, impotence.


Body as a whole: fever, dry mouth.


Endocrine and metabolic: thyroid nodules/thyroid cancer, syndrome of inappropriate antidiuretic hormone secretion (SIADH).


Vascular: vasculitis.

7Drug Interactions

Because of amiodarone's long half-life, expect drug interactions to persist for weeks to months after discontinuation of amiodarone.Drug interactions with amiodarone are described in Table 1 below.Table 1: Amiodarone Drug InteractionsConcomitant Drug Class/NameExamplesClinical CommentPharmacodynamic InteractionsQT Prolonging Drugs


class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, azole antifungals, halogenated inhalation anesthetic agentsIncreased risk of Torsade de Pointes. Avoid concomitant use.


Negative Chronotropes


digoxin, beta blockers, verapamil, diltiazem, clonidine, ivabradinePotentiates the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block. Monitor heart rate.Pharmacokinetic InteractionsCYP450 Inhibitors


grapefruit juice, certain fluoroquinolone  and macrolide antibiotics, azole antifungals, cimetidine, certainIncreased exposure of amiodarone. Avoid concomitant use.


protease inhibitorsCYP450 InducersSt. John's WortReduced amiodarone serum levels.Cyclosporine


Increased plasma levels of cyclosporine have been reported resulting in elevated creatinine, despite reduction of cyclosporine dose. Monitor cyclosporine drug levels and renal function with concomitant use.CholestyramineReduced amiodarone serum levels.Antiarrhythmics


quinidine, procainamide, flecainide


Reserve concomitant use for patients who are unresponsive to a single agent. Antiarrhythmic metabolism inhibited by amiodarone. Initiate antiarrhythmic at a lower than usual dose and monitor patient carefully. Reduce dose levels of previously administered antiarrhythmic by 30 to 50% for several days after transitioning to oral amiodarone. Evaluate continued need for antiarrhythmic.Digoxin


Increased digoxin concentration.


Reduce digoxin by half or discontinue. If continued, monitor for evidence of toxicity.


HMG-CoA


Reductase Inhibitors


simvastatin, lovastatin, atorvastatin


Increased plasma concentration of HMG-CoA reductase inhibitor.


Limit the dose of lovastatin to 40 mg.


Limit the coadministered dose of simvastatin to 20 mg.


Lower starting dose of other CYP3A4 substrates may be required.


Warfarin


Potentiates anticoagulant response and can result in serious or fatal bleeding. Coadministration increases prothrombin time by 100% after 3 to 4 days. Reduce warfarin dose by one-third to one- half and monitor prothrombin times.PhenytoinIncreased steady-state levels of phenytoin. Monitor phenytoin levels.Hepatitis C Direct Acting Antiviral


sofosbuvir


Cases of symptomatic bradyarrhythmia requiring pacemaker insertion have been reported in patients on oral maintenance amiodarone who initiated therapy with sofosbuvir.CYP3A Substrate


lidocaine


Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine given for local anesthesia. Monitor heart rate. A lower starting dose of lidocaine may be required.CYP3A Substrate


fentanyl


Fentanyl in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.

8.1Pregnancy

Risk SummaryAvailable data from postmarketing reports and published case series indicate that amiodarone use in pregnant women may increase the risk for fetal adverse effects including neonatal hypo- and hyperthyroidism, neonatal bradycardia, neurodevelopmental abnormalities, preterm birth and fetal growth restriction. Amiodarone and its metabolite, desethylamiodarone (DEA), cross the placenta. Untreated underlying arrhythmias, including ventricular arrhythmias, during pregnancy pose a risk to the mother and fetus


(see Clinical Considerations). In animal studies, administration of amiodarone to rabbits, rats, and mice during organogenesis resulted in embryo-fetal toxicity at doses less than the maximum recommended human maintenance dose


(see Data). Advise pregnant women of the potential risk to a fetus.


The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In theU.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and or embryo/fetal RiskThe incidence of ventricular tachycardia is increased and may be more symptomatic during pregnancy. Ventricular arrhythmias most often occur in pregnant women with underlying cardiomyopathy, congenital heart disease, valvular heart disease, or mitral valve prolapse. Most tachycardia episodes are initiated by ectopic beats and the occurrence of arrhythmia episodes may therefore, increase during pregnancy due to the increased propensity to ectopic activity. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state.Fetal/Neonatal adverse reactionsAmiodarone and its metabolite have been shown to cross the placenta. Adverse fetal effects associated with maternal amiodarone use during pregnancy may include neonatal bradycardia, QT prolongation, and periodic ventricular extrasystoles, neonatal hypothyroidism (with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure, neonatal hyperthyroxinemia, neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia, jerk nystagmus with synchronous head titubation, fetal growth restriction, and premature birth. Monitor the newborn for signs and symptoms of thyroid disorder and cardiac arrhythmias.Labor and DeliveryRisk of arrhythmias may increase during labor and delivery. Patients treated with amiodarone hydrochloride should be monitored continuously during labor and delivery


[see Warnings and Precautions (5.4)].


DataAnimal DataIn pregnant rats and rabbits during the period of organogenesis, amiodarone hydrochloride in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose


1) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose


1) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose


1) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose


1).


1 600 mg in a 60 kg patient (doses compared on a body surface area basis)

8.2Lactation

Risk SummaryAmiodarone and one of its major metabolites, DEA, are present in breastmilk at between 3.5% and 45% of the maternal weight-adjusted dosage of amiodarone. There are cases of hypothyroidism and bradycardia in breastfed infants, although it is unclear if these effects are due to amiodarone exposure in breastmilk. Breastfeeding is not recommended during treatment with amiodarone hydrochloride


[see Warnings and Precautions (5.6,5.7)].

8.3Females And Males Of Reproductive Potential

InfertilityBased on animal fertility studies, amiodarone hydrochloride may reduce female and male fertility. It is not known if this effect is reversible


[see Nonclinical Toxicology (13.1)].

8.4Pediatric Use

The safety and effectiveness of amiodarone hydrochloride in pediatric patients have not been established.

8.5Geriatric Use

Normal subjects over 65 years of age show lower clearances and increased drug half-life than younger subjects


[see Clinical Pharmacology (12.3)]. 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.

10Overdosage

There have been cases, some fatal, of amiodarone hydrochloride overdose.Monitor the patient's cardiac rhythm and blood pressure, and, if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Treat hypotension with inadequate tissue perfusion with positive inotropic and vasopressor agents. Neither amiodarone hydrochloride nor its metabolite is dialyzable.

11Description

Amiodarone hydrochloride, USP, is an antiarrhythmic drug, available for oral administration as yellow tablets containing 100 mg of amiodarone hydrochloride, yellow scored tablets containing 200 mg of amiodarone hydrochloride, and yellow scored tablets containing 400 mg of amiodarone hydrochloride. The inactive ingredients present in 100 mg, 200 mg, and 400 mg tablets are: lactose monohydrate, sodium starch glycolate, povidone, colloidal silicon dioxide, magnesium stearate, and pigment D&C yellow 10 aluminum lake. Amiodarone hydrochloride is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]- 3,5-diiodophenyl ketone hydrochloride.The structural formula is as follows:C25H29I2NO3·HClMolecular Weight:681.8Amiodarone hydrochloride is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight. FDA approved dissolution test specifications differ from USP.

12.1Mechanism Of Action

Amiodarone is considered a class III antiarrhythmic drug, but it possesses electrophysiologic characteristics of all four Vaughan Williams classes. Like class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like class II drugs, amiodarone exerts a noncompetitive antisympathetic action. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a class III effect. The negative chronotropic effect of amiodarone in nodal tissues is similar to the effect of class IV drugs. In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness. The antisympathetic action and the block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node. Its vasodilatory action can decrease cardiac workload and consequently myocardial oxygen consumption.Amiodarone hydrochloride prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Amiodarone hydrochloride increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of amiodarone hydrochloride as they are evidence of its pharmacological action, although amiodarone hydrochloride can cause marked sinus bradycardia or sinus arrest and heart block


[see Warnings and Precautions(5.4)].


HemodynamicsIn animal studies and after intravenous administration in man, amiodarone hydrochloride relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, amiodarone hydrochloride produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, amiodarone hydrochloride may have a mild negative inotropic effect.

12.2Pharmacodynamics

There is no well-established relationship between plasma concentration and effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects.Effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used.Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after amiodarone hydrochloride is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted.

12.3Pharmacokinetics

AbsorptionFollowing oral administration in humans, amiodarone hydrochloride is slowly and variably absorbed. The bioavailability of amiodarone is approximately 50%. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability.Food increases the rate and extent of absorption of amiodarone. The effects of food upon the bioavailability of amiodarone have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C


max) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (T


max) by 37%. The mean AUC and mean C


max of the major metabolite of amiodarone, DEA increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the T


max in the presence of food.


DistributionAmiodarone is highly protein-bound (approximately 96%). Amiodarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen.One major metabolite of amiodarone, DEA, has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA's precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular class III effects after oral amiodarone hydrochloride administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation.EliminationFollowing single dose administration in 12 healthy subjects, amiodarone exhibited multi- compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, amiodarone has been shown to have a biphasic elimination with an initial 50% reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55- day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat.The considerable inter-subject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Individualize maintenance doses of amiodarone hydrochloride


[see Dosage and Administration(2)].


MetabolismAmiodarone is metabolized to DEA by the cytochrome P450 (CYP) enzyme group, specifically CYP3A and CYP2C8. The CYP3A isoenzyme is present in both the liver and intestines.


In vitro, amiodarone and DEA exhibit a potential to inhibit CYP2C9, CYP2C19, CYP2D6, CYP3A, CYP2A6, CYP2B6 and CYP2C8. Amiodarone and DEA have also a potential to inhibit some transporters such as P- glycoprotein and organic cation transporter (OCT2).


ExcretionAmiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable.Specific PopulationsEffect of Age: Normal subjects over 65 years of age show lower clearances (about 100 mL/hr/kg) than younger subjects (about 150 mL/hr/kg) and an increase in t


½ from about 20 to 47 days.


Renal Impairment: Renal impairment does not influence the pharmacokinetics of amiodarone or DEA.


Hepatic Impairment: After a single dose of intravenous amiodarone to cirrhotic patients, significantly lower C


max and average concentration values are seen for DEA, but mean amiodarone levels are unchanged.


Cardiac Disease: In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal elimination t


½ of DEA is prolonged.


Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with oral amiodarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction.Drug Interactions:Effects of other agents on amiodaroneGrapefruit juice: Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and C


max by 84%, and decreased DEA to unquantifiable concentrations.


Cimetidineinhibits CYP3A and can increase serum amiodarone levels.


Cholestyraminereduces enterohepatic circulation of amiodarone thereby increasing its elimination. This results in reduced amiodarone serum levels and half-life.


Effects of amiodarone on agents:CYP3A substrates:Amiodarone taken concomitantly with


quinidine increases the 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.


Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A and its metabolism can be inhibited by amiodarone.


Metabolism of


lidocaine can be inhibited by amiodarone.


Cyclophosphamide is a prodrug, metabolized by CYP450 including CYP3A to an active metabolite. The metabolism of cyclophosphamide may be inhibited by amiodarone.


Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A to an active metabolite. A potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported.


Macrolide/ketolide antibiotics:Amiodarone can inhibit the metabolism


of macrolide/ketolide antibiotics (except for azithromycin) and systemic azole antifungal drugs.


P-glycoprotein substrates:Amiodarone taken concomitantly with


digoxin increases the serum digoxin concentration by 70% after one day.


Dabigatran etexilatewhen taken concomitantly with oral amiodarone can result in elevated serum concentration of dabigatran.


Dextromethorphanis a substrate for both CYP2D6 and CYP3A. Amiodarone inhibits CYP2D6. Chronic (> 2 weeks) oral amiodarone administration impairs metabolism of dextromethorphan can lead to increased serum concentrations.

13.1Carcinogenesis, Mutagenesis, Impairment Of Fertility

Amiodarone hydrochloride was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose


2).


Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with amiodarone hydrochloride were negative.In a study in which amiodarone hydrochloride was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately1.4 times the maximum recommended human maintenance dose


2).


2 600 mg in a 60 kg patient (dose compared on a body surface area basis)

16How Supplied/Storage And Handling

NDC: 63629-2076-1: 30 Tablets in a BOTTLE

17Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (


Medication Guide).


Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy


[see Use in Specific Populations(8.1)].Advise women that breastfeeding is not recommended during treatment with amiodarone hydrochloride


[see Use in Specific Populations (8.2)].Advise patients to avoid grapefruit juice and St. John's Wort.Advise patients to seek medical attention if they experience the signs and symptoms of pulmonary toxicity, worsening arrhythmia, bradycardia, visual impairment, or hypo- and hyperthyroidism.This product's label may have been updated. For full prescribing information, please visit www.cameronrx.com.Manufactured by:


Murty Pharmaceuticals, Inc., Lexington, KY 40509 USA


Distributed by:


Cameron Pharmaceuticals, LLC, Louisville, KY 40245 USA 


Revised: July 2020P192-02

* Please review the disclaimer below.