Adenosine

Pronunciation

Dosage Form: injection, solution

Indications and Usage for Adenosine

Adenosine Injection USP, is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately.

Adenosine Dosage and Administration

Therecommended Adenosine injection dose is 0.14 mg/kg/min infused oversix minutes(totaldose of0.84 mg/kg) (Table1).

 
 
Administer Adenosine injection onlyas a continuous peripheral intravenous infusion
Inject Thallium-201 at the midpoint of the Adenosine injection infusion (i.e.,after thefirst three minutes of Adenosine injection)
Thallium-201 is physicallycompatible with Adenosine injection and maybe injecteddirectly into the Adenosine injection infusion set
 
Inject Thallium-201 as close to the venous access as possible to preventan inadvertent increase in the dose of Adenosine injection (thecontents of the intravenous tubing)beingadministered

Visually inspect Adenosine injection for particulate matterand discoloration prior to administration. Do notadminister Adenosine injection if itcontains particulate matter or isdiscolored.


Thereareno data on the safetyor efficacyofalternative Adenosine injection infusion protocols. The safetyand efficacyof Adenosine injection administeredby the intracoronaryroute have not beenestablished.

Table 1 Dosage Chart for Adenosine Injection

Patient Weight
(kilograms)

 
Infusion Rate
(mL per minute over6
minutesfor totaldose of

0.84 mg/kg)

45

2.1

50

2.3

55

2.6

60

2.8

65

3

70

3.3

75

3.5

80

3.8

85

4

90

4.2

Thenomogramdisplayed in Table 1 wasderived from thefollowing generalformula:

Dosage Forms and Strengths

Adenosine for injection is supplied as 20 mLand 30 mLsingle-use vialscontaininga sterile, nonpyrogenic,clear solution ofAdenosine 3 mg/mL.

Contraindications

Adenosineis contraindicated in patients with:

 
 
Second-or third-degree AV block(except inpatients with afunctioningartificialpacemaker)[see Warningsand Precautions (5.2)]
Sinus node disease, such assicksinus syndrome orsymptomatic bradycardia(except in patients witha functioning artificialpacemaker)[see Warnings and Precautions (5.2)]
Known orsuspectedbronchoconstrictive orbronchospastic lungdisease(e.g., asthma) [see Warnings and Precautions (5.3)]
Known hypersensitivity to Adenosine [see Warningsand Precautions (5.7)]

Warnings and Precautions

Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction

Fatalandnonfatalcardiac arrest,sustained ventricular tachycardia(requiringresuscitation), and myocardial infarction have occurredfollowing Adenosine infusion. Avoiduse in patients with symptoms orsigns of acute myocardial ischemia, forexample, unstableangina orcardiovascular instability; these patients maybe at greater riskof serious cardiovascularreactions to Adenosine. Appropriateresuscitative measures shouldbe available [see Overdosage (10)].

Sinoatrial and Atrioventricular Nodal Block

Adenosine exerts adirect depressant effecton the SAand AVnodes and maycause first-, second-or third-degree AV block, orsinus bradycardia. In clinical trials, approximately6%ofpatientsdeveloped AVblockfollowingAdenosine administration(first-degree heart blockdeveloped in 3%, second-degree in 3%,and third-degree in 0.8% of patients)[see Clinical Trials Experience (6.1)].

Use Adenosinewithcaution in patients with pre-existingfirst-degree AV block orbundle branch block. Do notuse in patients with high-grade AV blockor sinus nodedysfunction(except in patients with afunctioningartificialpacemaker). Discontinue Adenosine inanypatient whodevelops persistentorsymptomatic high-grade AV block.

Bronchoconstriction

Adenosine administration cancause dyspnea, bronchoconstriction, and respiratorycompromise. Adenosineshould be used with caution in patients withobstructive lungdisease not associated withbronchoconstriction(e.g., emphysema, bronchitis). Do not use inpatients with bronchoconstriction or bronchospasm(e.g., asthma). Discontinue Adenosinein anypatient whodevelops severe respiratorydifficulties. Resuscitative measures should be available prior to Adenosine administration[see Clinical Trials Experience (6.1), Overdosage (10), and Clinical Pharmacology (12.2)].

Hypotension

Adenosine is a potent peripheral vasodilator and can induce significant hypotension. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. Discontinue Adenosine in any patient who develops persistent or symptomatic hypotension.

Cerebrovascular Accident

Hemorrhagic and ischemiccerebrovascular accidents have occurred. Hemodynamic effects ofAdenosine including hypotension orhypertension can be associated with these adversereactions. [see Warnings and Precautions (5.4) and (5.9)].

Seizures

New-onset orrecurrence ofconvulsive seizures has occurred followingAdenosine. Some seizuresare prolonged and requireemergentanticonvulsive management. Aminophylline may increase the riskofseizures associated with Adenosine.Methylxanthine use isnotrecommended in patients who experienceseizures in association withAdenosine administration[see Overdosage (10)].

Hypersensitivity

Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Symptomatic treatment may be required. Have personnel and appropriate treatment available. Resuscitative measures may be necessary if symptoms progress [see Post-Marketing Experience (6.2)].

Atrial Fibrillation

Adenosine can cause atrial fibrillation in patients with or without a history of atrial fibrillation. Atrial fibrillation typically began 1.5 to 3 minutes after initiation of Adenosine, lasted for 15 seconds to 6 hours, and spontaneously converted to normal sinus rhythm [see Post-Marketing Experience (6.2)].

Hypertension

Adenosine can induce clinically significant increases in systolic and diastolic blood pressure. Most increases resolved spontaneously within several minutes, but in some cases, hypertension lasted for several hours [see Clinical Trials Experience (6.1)].

Adverse Reactions

Thefollowingadversereactions are discussed in moredetail in other sections of the prescribing information:

 
Fatal Cardiac Arrest, Ventricular Arrhythmias, andMyocardial Infarction[see Warnings and Precautions (5.1)]
 
Sinoatrialand Atrioventricular Nodal Block[see Warningsand Precautions (5.2)]
 
Bronchoconstriction[see Warnings and Precautions (5.3)]
 
Hypotension[see Warnings and Precautions (5.4)]
 
Cerebrovascular Accident[see Warningsand Precautions (5.5)]
 
Seizures[see Warningsand Precautions (5.6)]
 
Hypersensitivity[see Warnings and Precautions (5.7)]
 
Atrialfibrillation[see Warningsand Precautions (5.8)]
 
Hypertension[see Warnings and Precautions (5.9)]

Clinical Trials Experience

Because clinical trials are conducted under widely varyingconditions,adversereactionrates observed in theclinical trials ofa drugcannotbedirectlycompared torates in theclinical trials ofanotherdrugand maynotreflect the rates observed in practice.

Thefollowingadversereactions, with an incidenceofat least 1%, were reported with Adenosine among1,421 patients in clinical trials.11% of the adverse reactions occurred several hoursafterAdenosine administration. 8% of the adverse reactions began with Adenosine infusion and persisted forup to 24 hours.

The mostcommon (incidence ≥10%)adversereactions to Adenosineareflushing, chest discomfort, shortness of breath, headache, throat,neckor jawdiscomfort, gastrointestinal discomfort, and dizziness (Table 2).

Table 2 Adverse Reactions in Clinical Trials (Frequency ≥ 1%)

 
Adverse Reactions

Adenosine

N=1,421

 
Flushing
 
44%
 
Chest discomfort
 
40%
 
Dyspnea
 
28%
 
Headache
 
18%
 
Throat, neckor jaw discomfort
 
15%
 
Gastrointestinaldiscomfort
 
13%
 
Lightheadedness/dizziness
 
12%
 
Upperextremitydiscomfort
 
4%
 
ST segmentdepression
 
3%
 
First-degree AV block
 
3%
 
Second-degree AV block
 
3%
 
Paresthesia
 
2%
 
Hypotension
 
2%
 
Nervousness
 
2%
 
Arrhythmias
 
1%

Post-Marketing Experience

Thefollowingadversereactions have been reportedfrom marketingexperience with Adenosine. Because these reactions arereported voluntarily froma population ofuncertainsize, are associated withconcomitantdiseases and multiple drug therapiesand surgicalprocedures, it is not always possible to reliablyestimate theirfrequencyorestablish acausal relationship to drugexposure.

Cardiac Disorders: car di ac a r re st , atria l fi b rillati on, c ar di ac f ail ure, my ocard ia l
in f a r cti on, ta c hy card i a, v e ntri c ul ar a r rh ythmi a
G as tr o int e sti n a l Di s o rd e r s : naus e a and v o miti ng
G ener a l Di sor d e r s and Admi n i s tr a ti on Sit e C ond iti o ns : che s t p ai n, inj ec ti on s it e re a c ti on, i nf u s i on s it e p a i n
Imm une Sy s t em Di sord e r s : h y persen sitivity
N er v ous Sy s t em Di sord e r s : cer e bro v asc ula r a c c id ent in c l u di ng i n t ra c ra nia l he m or r ha ge ,
se iz ure a ctivit y in c lu d i ng to n i c - c l on i c ( g rand m a l ) s eiz ures, l o s s
of co n s ci ous n ess
R esp i ra t or y , T ho r ac i c and Med i a stin al Di s o rd e rs: bronc h osp a s m , resp i r at ory ar r es t , th ro a t tig h t n e ss

Drug Interactions

Effects ofOther Drugs on Adenosine

 
The vasoactive effectsof Adenosineare inhibitedbyAdenosinereceptorantagonists, (suchas methylxanthines (e.g., caffeine,aminophylline, and theophylline). The safetyand efficacyofAdenosine in the presenceof these agents has notbeen systematicallyevaluated[see Overdosage (10)].
 
The vasoactive effectsofAdenosineare potentiated bynucleoside transport inhibitorssuch as dipyridamole. The safetyand efficacyof Adenosine in thepresence ofdipyridamole has not beensystematicallyevaluated.
 
Wheneverpossible, drugs that might inhibit oraugment the effects ofAdenosine should be withheldforat least five half-lives prior to the use ofAdenosine.

Effects of Adenosine on Other Drugs

Adenosineinjection has been given withothercardioactive drugs (suchas beta adrenergicblockingagents, cardiac glycosides, andcalciumchannelblockers) withoutapparentadverse interactions, but its effectiveness with these agents has notbeen systematicallyevaluated. Becauseof the potentialforadditive orsynergistic depressant effects on the SAand AV nodes,however, Adenosineshould beused withcaution in thepresence of these agents[see Warningsand Precautions (5.2)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects

Pregnancy Category C

Animalreproduction studies have notbeen conducted with Adenosine; nor have studies been performed in pregnant women. Because it is not known whether Adenosine cancause fetalharm when administered to pregnant women, Adenosineshould beusedduringpregnancyonly ifclearlyneeded.

Nursing Mothers

It is not known whether Adenosine is excreted in human milk. Because manydrugs are excreted in human milkand because of the potentialforseriousadversereactions from Adenosine innursing infants, the decision to interruptnursing after administration of Adenosineor not to administer Adenosine, should take into account the importance of the drug to the mother.

Pediatric Use

Thesafetyand effectiveness of Adenosine in patients less than 18 yearsofage have notbeenestablished.

Geriatric Use

Clinical studies with Adenosine did not includesufficientnumbersof subjects aged younger than 65 years todetermine whether theyrespond differently. Otherreported experience has not revealed clinicallyrelevantdifferencesof the response of elderly incomparison to youngerpatients.

Overdosage

Thehalf-lifeof Adenosine is less than 10 secondsand adverse reactions of Adenosineusuallyresolve quickly when the infusion isdiscontinued,although delayed orpersistentreactions have been observed. Methylxanthines, suchas caffeine, aminophylline,and theophylline,arecompetitive Adenosinereceptorantagonists and theophylline has been used to terminate persistent adverse reactions. In clinical trials, theophylline (50 to 125 mg slow intravenous injection) was used to attenuate Adenosine adverse reactions inapproximately2%ofpatients. Methylxanthine use is notrecommended in patients who experienceseizures inassociation with Adenosine[see Drug Interactions (7.1)].

Adenosine Description

Adenosine, USP is anendogenous nucleosideand is chemicallydescribed as 6-Amino-9-ï¢-D-ribofuranosyl-9H-purine. Adenosine, USP has the followingstructuralformula:

The molecularformula forAdenosine is C10H13N5O4 and its molecular weight is267.24.

Adenosine, USP is a white crystalline powder. It issoluble in waterandpractically insoluble inalcohol. Solubility increases by warmingand lowering the pHof thesolution.

Each Adenosine injection USP vialcontains a sterile, non-pyrogenicsolution ofAdenosine, USP 3 mg/mLand sodiumchloride9 mg/mL in waterforinjection, q.s. withpHbetween 4.5and 7.5.

Adenosine - Clinical Pharmacology

Mechanism of Action

Adenosine causes cardiac vasodilation which increases cardiac blood flow. Adenosine is thought to exert its pharmacological effects through activation ofpurinereceptors(cell-surface A1and A2Adenosine receptors). Although the exact mechanismby which Adenosinereceptoractivation relaxes vascularsmooth muscle is not known, there is evidence to supportboth inhibition of the slow inward calciumcurrentreducingcalciumuptake, and activation ofadenylatecyclase through A2receptors in smooth musclecells. Adenosine mayalso lessen vascular tone by modulatingsympathetic neurotransmission. The intracellularuptake ofAdenosine is mediated bya specific transmembrane nucleoside transport system. Once inside thecell, Adenosine israpidlyphosphorylated byAdenosine kinase to Adenosine monophosphate, or deaminatedbyAdenosine deaminase to inosine. These intracellular metabolites ofAdenosineare not vasoactive.

Myocardialuptake of thallium-201 is directlyproportional to coronaryblood flow. Since Adenosinesignificantly increases bloodflow in normalcoronaryarteries with littleor no increase instenotic arteries, Adenosine causes relatively less thallium-201 uptake in vascular territoriessuppliedbystenoticcoronary arteries i.e., a greater difference is seen after Adenosine betweenareas served bynormaland areasserved bystenotic vessels than is seen prior to Adenosine.

Pharmacodynamics

Hemodynamic Effects

Adenosine produces adirectnegative chronotropic, dromotropic and inotropic effecton theheart,presumablydue to A1-receptoragonism, and produces peripheral vasodilation,presumablydue to A2-receptoragonism. Theneteffectof Adenosine inhumans is typicallya mild to moderate reduction insystolic, diastolic and mean arterialbloodpressure associated witha reflex increase in heartrate. Rarely, significanthypotension and tachycardia have been observed[see Warnings and Precautions (5.4)].

Pharmacokinetics

Distribution

IntravenouslyadministeredAdenosinedistributes from the circulation via cellular uptake, primarilybyerythrocytes and vascularendothelialcells. This process involves a specific transmembrane nucleosidecarriersystem that is reversible, nonconcentrative, and bidirectionallysymmetrical.

Metabolism

Intracellular Adenosine is metabolized either via phosphorylation to Adenosine monophosphate byAdenosine kinase, or via deamination to inosine by Adenosine deaminase in thecytosol. Since Adenosine kinase has a lower Kmand Vmaxthan Adenosinedeaminase, deaminationplays asignificant role only when cytosolic Adenosine saturates the phosphorylation pathway. Inosine formed bydeamination ofAdenosinecan leave the cell intact orcan bedegraded to hypoxanthine, xanthine,and ultimatelyuric acid. Adenosine monophosphateformed byphosphorylation ofAdenosine is incorporated into thehigh-energyphosphatepool.

Elimination

While extracellular Adenosine isprimarilycleared fromplasma bycellularuptake with ahalf-lifeof less than10 seconds in whole blood, excessive amounts maybe deaminatedbyan ecto-formofAdenosine deaminase.

Specific Populations

RenalImpairment
As Adenosine does notrequire renalfunctionfor itsactivationor inactivation,renal impairment wouldnotbeexpected to alter itseffectivenessor tolerability.

Hepatic Impairment
As Adenosine does notrequirehepaticfunctionfor its activation or inactivation,hepatic impairment wouldnotbe expected to alter its effectivenessor tolerability.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have notbeen performed to evaluateAdenosine’scarcinogenic potential orpotential effectson fertility. Adenosine wasnegative for genotoxic potential in the Salmonella (Ames Test) and MammalianMicrosome Assay.

Adenosine, however, like othernucleosides at millimolarconcentrationspresentforseveraldoubling times ofcells in culture, is known to produce a varietyof chromosomalalterations.

Clinical Studies

In two crossover comparative studies involving319 subjects whocould exercise (including106 healthy volunteers and 213 patients with known orsuspected coronarydisease), Adenosineand exercise thallium images were comparedby blinded observers. The images were concordantfor the presenceof perfusion defects in 85.5% of cases by globalanalysis (patientbypatient)and up to 93% of cases based on vascular territories.

In the two studies, 193patientsalso hadrecentcoronaryarteriographyforcomparison (healthy volunteers were not catheterized). Thesensitivityfordetectingangiographicallysignificant disease (≥50%reduction in the luminal diameter of at leastone major vessel) was 64%for Adenosine and 64%forexercise testing. The specificity was 54%for Adenosine and65%forexercise testing. The 95%confidence limitsfor Adenosinesensitivity were56% to 78%and for specificity were 37% to 71%.

Intracoronary Doppler flowcatheter studieshave demonstrated thata dose of intravenous Adenosine of0.14 mg/kg/min produces maximumcoronaryhyperemia (relative to intracoronarypapaverine) inapproximately95%ofcases within two to three minutesof the onsetof the infusion. Coronarybloodflow velocityreturns to basal levels withinone to two minutes ofdiscontinuing the Adenosine infusion.

How Supplied/Storage and Handling

How Supplied

Adenosine Injection USP is supplied as 20 mL and 30 mL vials of sterile, nonpyrogenic, preservative-free solution in normal saline.

NDC Number

Adenosine Injection USP

0703-8776-01

20 mL single-use vial packaged individually

0703-8777-01

30 mL single-use vial packaged individually

Storage and Handling

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature.]
Do not refrigerate as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use
Discard unused portion

Package/Label Display Panel

Adenosine Injection USP 3 mg/mL, 20mL Single-Use Carton Text

NDC 0703-8776-01 Rx only

Adenosine

Injection USP

60 mg/20 mL

(3 mg/mL)

FOR INTRAVENOUS INFUSION

ONLY

Sterile, Nonpyrogenic

20 mL Single-Use Vial

TEVA

Package/Label Display Panel

Adenosine Injection USP 3 mg/mL, 30mL Single-Use Carton Text

NDC 0703-8777-01 Rx only

Adenosine

Injection USP

90 mg/30 mL

(3 mg/mL)

FOR INTRAVENOUS INFUSION

ONLY

Sterile, Nonpyrogenic

30 mL Single-Use Vial

TEVA

Adenosine 
Adenosine injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0703-8776
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Adenosine (Adenosine) Adenosine 3 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
SODIUM CHLORIDE  
WATER  
Packaging
# Item Code Package Description
1 NDC:0703-8776-01 1 VIAL, SINGLE-USE in 1 CARTON
1 20 mL in 1 VIAL, SINGLE-USE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077425 09/23/2013
Adenosine 
Adenosine injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0703-8777
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Adenosine (Adenosine) Adenosine 3 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
SODIUM CHLORIDE  
WATER  
Packaging
# Item Code Package Description
1 NDC:0703-8777-01 1 VIAL, SINGLE-USE in 1 CARTON
1 30 mL in 1 VIAL, SINGLE-USE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077425 09/23/2013
Labeler - Teva Parenteral Medicines, Inc. (794362533)
Revised: 10/2014
 
Teva Parenteral Medicines, Inc.
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