ADENOSINE: 706 Adverse Event Reports & Safety Profile

DESCRIPTION: Adenosine is an endogenous nucleoside occurring in all cells of the body. It is chemically 6-amino-9-β-D-ribofuranosyl-9-H-purine and has the following structural formula: C 10 H 13 N 5 O 4 M.W.

267.24 Adenosine is a white crystalline powder. It is soluble in water and practically insoluble in alcohol. Solubility increases by warming and lowering the pH. Adenosine is not chemically related to other antiarrhythmic drugs. Adenosine injection, USP is a sterile, nonpyrogenic solution for rapid bolus intravenous injection. Each mL contains 3 mg adenosine and 9 mg sodium chloride in water for injection. The pH of the solution is between 4.5 and 7.5.

The

TopPac ® plastic syringe is molded from a specially formulated cyclo olefin copolymer. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts which have been toxicologically assessed and are within the safety margins. structure

INDICATIONS AND USAGE: Intravenous adenosine injection, USP is indicated for the following: Conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT), including that associated with accessory bypass tracts (Wolff-Parkinson-White Syndrome). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver), should be attempted prior to adenosine injection, USP administration. It is important to be sure the adenosine injection, USP solution actually reaches the systemic circulation (see DOSAGE AND ADMINISTRATION ). Adenosine injection, USP does not convert atrial flutter, atrial fibrillation, or ventricular tachycardia to normal sinus rhythm. In the presence of atrial flutter or atrial fibrillation, a transient modest slowing of ventricular response may occur immediately following adenosine injection, USP administration.

DOSAGE AND ADMINISTRATION: For rapid bolus intravenous use only. Adenosine injection, USP should be given as a rapid bolus by the peripheral intravenous route. To be certain the solution reaches the systemic circulation, it should be administered either directly into a vein or, if given into an intravenous line, it should be given as close to the patient as possible and followed by a rapid saline flush.

Adult Patients

The dose recommendation is based on clinical studies with peripheral venous bolus dosing. Central venous (CVP or other) administration of adenosine injection, USP has not been systematically studied. The recommended intravenous doses for adults are as follows: Initial dose: 6 mg given as a rapid intravenous bolus (administered over a 1 to 2 second period). Repeat administration: If the first dose does not result in elimination of the supraventricular tachycardia within 1 to 2 minutes, 12 mg should be given as a rapid intravenous bolus.

This

12 mg dose may be repeated a second time if required.

Pediatric Patients

The dosages used in neonates, infants, children and adolescents were equivalent to those administered to adults on a weight basis.

Pediatric

Patients with a Body Weight less than 50 kg: Initial dose: Give 0.05 mg/kg to 0.1 mg/kg as a rapid intravenous bolus given either centrally or peripherally. A saline flush should follow. Repeat administration: If conversion of paroxysmal supraventricular tachycardia does not occur within 1 to 2 minutes, additional bolus injections of adenosine can be administered at incrementally higher doses, increasing the amount given by 0.05 mg/kg to 0.1 mg/kg. Follow each bolus with a saline flush. This process should continue until sinus rhythm is established or a maximum single dose of 0.3 mg/kg is used.

Pediatric

Patients with a Body Weight greater than or equal to 50 kg: Administer the adult dose. Doses greater than 12 mg are not recommended for adult and pediatric patients. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Adult Patients

The dose recommendation is based on clinical studies with peripheral venous bolus dosing. Central venous (CVP or other) administration of adenosine injection, USP has not been systematically studied. The recommended intravenous doses for adults are as follows: Initial dose: 6 mg given as a rapid intravenous bolus (administered over a 1 to 2 second period). Repeat administration: If the first dose does not result in elimination of the supraventricular tachycardia within 1 to 2 minutes, 12 mg should be given as a rapid intravenous bolus.

This

12 mg dose may be repeated a second time if required.

Pediatric Patients

The dosages used in neonates, infants, children and adolescents were equivalent to those administered to adults on a weight basis.

Pediatric

Patients with a Body Weight less than 50 kg: Initial dose: Give 0.05 mg/kg to 0.1 mg/kg as a rapid intravenous bolus given either centrally or peripherally. A saline flush should follow. Repeat administration: If conversion of paroxysmal supraventricular tachycardia does not occur within 1 to 2 minutes, additional bolus injections of adenosine can be administered at incrementally higher doses, increasing the amount given by 0.05 mg/kg to 0.1 mg/kg. Follow each bolus with a saline flush. This process should continue until sinus rhythm is established or a maximum single dose of 0.3 mg/kg is used.

Pediatric

Patients with a Body Weight greater than or equal to 50 kg: Administer the adult dose. Doses greater than 12 mg are not recommended for adult and pediatric patients. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Adenosine injection is contraindicated in patients with: Second- or third-degree AV block (except in patients with a functioning artificial pacemaker) [see Warnings and Precautions (5.2) ] Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker) [see Warnings and Precautions (5.2) ] Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma) [see Warnings and Precautions (5.3) ] Known hypersensitivity to adenosine injection [see Warnings and Precautions (5.7) ] Second- or third-degree AV block (except in patients with a functioning artificial pacemaker) ( 4 ) Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker) ( 4 ) Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma) ( 4 ) Known hypersensitivity to adenosine injection ( 4 )

REACTIONS The following adverse reactions are discussed in more detail in other sections of the prescribing information: Fatal Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction [see Warnings and Precautions ( 5.1 )] Sinoatrial and Atrioventricular Nodal Block [see Warnings and Precautions ( 5.2 )] Bronchoconstriction [see Warnings and Precautions ( 5.3 )] Hypotension [see Warnings and Precautions ( 5.4 )]

Cerebrovascular

Accident [see Warnings and Precautions ( 5.5 )] Seizures [see Warnings and Precautions ( 5.6 )] Hypersensitivity [see Warnings and Precautions ( 5.7 )] Atrial fibrillation [see Warnings and Precautions ( 5.8 )] Hypertension [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥ 10%) are: flushing; chest discomfort; shortness of breath; headache; throat, neck or jaw discomfort; gastrointestinal discomfort; and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical 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. The following adverse reactions, with an incidence of at least 1%, were reported with adenosine among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after adenosine administration. 8% of the adverse reactions began with adenosine infusion and persisted for up to 24 hours. The most common (incidence ≥ 10%) adverse reactions to adenosine are flushing, chest discomfort, shortness of breath, headache, throat, neck or jaw discomfort, 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, neck or jaw discomfort 15% Gastrointestinal discomfort 13% Lightheadedness/dizziness 12% Upper extremity discomfort 4% ST segment depression 3% First-degree AV block 3% Second-degree AV block 3% Paresthesia 2% Hypotension 2% Nervousness 2% Arrhythmias 1% Adverse reactions to adenosine of any severity reported in less than 1% of patients include: Body as a Whole: back discomfort, lower extremity discomfort, weakness Cardiovascular System: myocardial infarction, ventricular arrhythmia, third-degree AV block, bradycardia, palpitation, sinus exit block, sinus pause, T-wave changes, hypertension (systolic blood pressure > 200 mm Hg)

Respiratory

System: cough Central Nervous System: drowsiness, emotional instability, tremors Genital/Urinary System: vaginal pressure, urgency Special Senses: blurred vision, dry mouth, ear discomfort, metallic taste, nasal congestion, scotomas, tongue discomfort

6.2 Post-Marketing Experience The following adverse reactions have been reported from marketing experience with adenosine. Because these reactions are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac

Disorders: cardiac arrest, atrial fibrillation, cardiac failure, myocardial infarction, tachycardia, ventricular arrhythmia Gastrointestinal Disorders: nausea and vomiting General Disorders and Administration Site Conditions: chest pain, injection site reaction, infusion site pain Immune System Disorders: hypersensitivity Nervous System Disorders: cerebrovascular accident including intracranial hemorrhage, seizure activity including tonic-clonic (grand mal) seizures, loss of consciousness Respiratory, Thoracic and Mediastinal Disorders: bronchospasm, respiratory arrest, throat tightness

6.1 Clinical 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. The following adverse reactions, with an incidence of at least 1%, were reported with adenosine among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after adenosine administration. 8% of the adverse reactions began with adenosine infusion and persisted for up to 24 hours. The most common (incidence ≥ 10%) adverse reactions to adenosine are flushing, chest discomfort, shortness of breath, headache, throat, neck or jaw discomfort, 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, neck or jaw discomfort 15% Gastrointestinal discomfort 13% Lightheadedness/dizziness 12% Upper extremity discomfort 4% ST segment depression 3% First-degree AV block 3% Second-degree AV block 3% Paresthesia 2% Hypotension 2% Nervousness 2% Arrhythmias 1% Adverse reactions to adenosine of any severity reported in less than 1% of patients include: Body as a Whole: back discomfort, lower extremity discomfort, weakness Cardiovascular System: myocardial infarction, ventricular arrhythmia, third-degree AV block, bradycardia, palpitation, sinus exit block, sinus pause, T-wave changes, hypertension (systolic blood pressure > 200 mm Hg)

Respiratory

System: cough Central Nervous System: drowsiness, emotional instability, tremors Genital/Urinary System: vaginal pressure, urgency Special Senses: blurred vision, dry mouth, ear discomfort, metallic taste, nasal congestion, scotomas, tongue discomfort

6.2 Post-Marketing Experience The following adverse reactions have been reported from marketing experience with adenosine. Because these reactions are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac

Disorders: cardiac arrest, atrial fibrillation, cardiac failure, myocardial infarction, tachycardia, ventricular arrhythmia Gastrointestinal Disorders: nausea and vomiting General Disorders and Administration Site Conditions: chest pain, injection site reaction, infusion site pain Immune System Disorders: hypersensitivity Nervous System Disorders: cerebrovascular accident including intracranial hemorrhage, seizure activity including tonic-clonic (grand mal) seizures, loss of consciousness Respiratory, Thoracic and Mediastinal Disorders: bronchospasm, respiratory arrest, throat tightness

AND PRECAUTIONS Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction . Fatal cardiac events have occurred. Avoid use in patients with symptoms or signs of acute myocardial ischemia. Appropriate resuscitative measures should be available ( 5.1 ) Sinoatrial (SA) and Atrioventricular (AV)

Nodal

Block . First-, second- or third-degree AV block, or sinus bradycardia can occur. Discontinue adenosine if patient develops persistent or symptomatic high-grade AV block ( 5.2 ) Bronchoconstriction . Can induce dyspnea, bronchoconstriction, and respiratory compromise, especially in patients with obstructive pulmonary disease. Discontinue adenosine if patient develops severe respiratory difficulties ( 5.3 ) Hypotension . Significant hypotension can occur. Discontinue adenosine if patient develops persistent or symptomatic hypotension ( 5.4 )

Cerebrovascular

Accidents . Hemorrhagic and ischemic cerebrovascular accidents have occurred ( 5.5 ) Seizures . New onset or recurrence of convulsive seizures have occurred. Use of methylxanthines (e.g., caffeine, aminophylline and theophylline) is not recommended in patients who experience seizures in association with adenosine ( 5.6 ) Hypersensitivity . Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Have personnel and resuscitative equipment immediately available ( 5.7 )

Atrial

Fibrillation . Reported in patients with or without a history of atrial fibrillation ( 5.8 ) Hypertension . Clinically significant increases in systolic and diastolic pressure have been observed ( 5.9 )

5.1 Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction Fatal and nonfatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and myocardial infarction have occurred following adenosine infusion. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example, unstable angina or cardiovascular instability; these patients may be at greater risk of serious cardiovascular reactions to adenosine. Appropriate resuscitative measures should be available <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span> .

5.2 Sinoatrial and Atrioventricular Nodal Block Adenosine exerts a direct depressant effect on the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia. In clinical trials, approximately 6% of patients developed AV block following adenosine administration (first-degree heart block developed in 3%, second-degree in 3%, and third-degree in 0.8% of patients) <span class="opacity-50 text-xs">[see Clinical Trials Experience ( 6.1 )]</span> . Use adenosine with caution in patients with pre-existing first-degree AV block or bundle branch block. Do not use in patients with high-grade AV block or sinus node dysfunction (except in patients with a functioning artificial pacemaker). Discontinue adenosine in any patient who develops persistent or symptomatic high-grade AV block.

5.3 Bronchoconstriction Adenosine administration can cause dyspnea, bronchoconstriction, and respiratory compromise. Adenosine should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis). Do not use in patients with bronchoconstriction or bronchospasm (e.g., asthma). Discontinue adenosine in any patient who develops severe respiratory difficulties. Resuscitative measures should be available prior to adenosine administration <span class="opacity-50 text-xs">[see Clinical Trials Experience ( 6.1 ), Overdosage ( 10 ), and Clinical Pharmacology ( 12.2 )]</span>.

5.4 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.

5.5 Cerebrovascular Accident Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of adenosine including hypotension or hypertension can be associated with these adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 ) and ( 5.9 )]</span> .

5.6 Seizures New-onset or recurrence of convulsive seizures has occurred following adenosine. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with adenosine. Methylxanthine use is not recommended in patients who experience seizures in association with adenosine administration <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span>.

5.7 Hypersensitivity, including Anaphylaxis 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 <span class="opacity-50 text-xs">[see Post-Marketing Experience ( 6.2 )]</span>.

5.8 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 <span class="opacity-50 text-xs">[see Post-Marketing Experience ( 6.2 )]</span> .

5.9 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 <span class="opacity-50 text-xs">[see Clinical Trials Experience ( 6.1 )]</span> .

5.1 Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction Fatal and nonfatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and myocardial infarction have occurred following adenosine infusion. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example, unstable angina or cardiovascular instability; these patients may be at greater risk of serious cardiovascular reactions to adenosine. Appropriate resuscitative measures should be available <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span> .

5.2 Sinoatrial and Atrioventricular Nodal Block Adenosine exerts a direct depressant effect on the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia. In clinical trials, approximately 6% of patients developed AV block following adenosine administration (first-degree heart block developed in 3%, second-degree in 3%, and third-degree in 0.8% of patients) <span class="opacity-50 text-xs">[see Clinical Trials Experience ( 6.1 )]</span> . Use adenosine with caution in patients with pre-existing first-degree AV block or bundle branch block. Do not use in patients with high-grade AV block or sinus node dysfunction (except in patients with a functioning artificial pacemaker). Discontinue adenosine in any patient who develops persistent or symptomatic high-grade AV block.

5.3 Bronchoconstriction Adenosine administration can cause dyspnea, bronchoconstriction, and respiratory compromise. Adenosine should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis). Do not use in patients with bronchoconstriction or bronchospasm (e.g., asthma). Discontinue adenosine in any patient who develops severe respiratory difficulties. Resuscitative measures should be available prior to adenosine administration <span class="opacity-50 text-xs">[see Clinical Trials Experience ( 6.1 ), Overdosage ( 10 ), and Clinical Pharmacology ( 12.2 )]</span>.

5.4 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.

5.5 Cerebrovascular Accident Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of adenosine including hypotension or hypertension can be associated with these adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 ) and ( 5.9 )]</span> .

5.6 Seizures New-onset or recurrence of convulsive seizures has occurred following adenosine. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with adenosine. Methylxanthine use is not recommended in patients who experience seizures in association with adenosine administration <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span>.

5.7 Hypersensitivity, including Anaphylaxis 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 <span class="opacity-50 text-xs">[see Post-Marketing Experience ( 6.2 )]</span>.

5.8 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 <span class="opacity-50 text-xs">[see Post-Marketing Experience ( 6.2 )]</span> .

5.9 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 <span class="opacity-50 text-xs">[see Clinical Trials Experience ( 6.1 )]</span> .

PRECAUTIONS: Drug Interactions Intravenous adenosine injection, USP has been effectively administered in the presence of other cardioactive drugs, such as quinidine, beta-adrenergic blocking agents, calcium channel blocking agents, and angiotensin converting enzyme inhibitors, without any change in the adverse reaction profile. Digoxin and verapamil use may be rarely associated with ventricular fibrillation when combined with adenosine injection, USP (see WARNINGS ). Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, adenosine injection, USP should be used with caution in the presence of these agents. The use of adenosine injection, USP in patients receiving digitalis may be rarely associated with ventricular fibrillation (see WARNINGS ). The effects of adenosine are antagonized by methylxanthines such as caffeine and theophylline. In the presence of these methylxanthines, larger doses of adenosine may be required or adenosine may not be effective. Adenosine effects are potentiated by dipyridamole. Thus, smaller doses of adenosine may be effective in the presence of dipyridamole. Carbamazepine has been reported to increase the degree of heart block produced by other agents. As the primary effect of adenosine is to decrease conduction through the A-V node, higher degrees of heart block may be produced in the presence of carbamazepine. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals have not been performed to evaluate the carcinogenic potential of adenosine injection, USP. Adenosine was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay. Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations. Fertility studies in animals have not been conducted with adenosine.

Pregnancy

Category C Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. As adenosine is a naturally occurring material, widely dispersed throughout the body, no fetal effects would be anticipated. However, since it is not known whether adenosine injection, USP can cause fetal harm when administered to pregnant women, adenosine injection, USP should be used during pregnancy only if clearly needed.

Pediatric

Use No controlled studies have been conducted in pediatric patients to establish the safety and efficacy of adenosine injection, USP for the conversion of paroxysmal supraventricular tachycardia (PSVT). However, intravenous adenosine has been used for the treatment of PSVT in neonates, infants, children and adolescents (see DOSAGE AND ADMINISTRATION ).

Geriatric Use

Clinical studies of adenosine injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, adenosine injection, USP in geriatric patients should be used with caution since this population may have a diminished cardiac function, nodal dysfunction, concomitant diseases or drug therapy that may alter hemodynamic function and produce severe bradycardia or AV block.

Drug Interactions

Intravenous adenosine injection, USP has been effectively administered in the presence of other cardioactive drugs, such as quinidine, beta-adrenergic blocking agents, calcium channel blocking agents, and angiotensin converting enzyme inhibitors, without any change in the adverse reaction profile. Digoxin and verapamil use may be rarely associated with ventricular fibrillation when combined with adenosine injection, USP (see WARNINGS ). Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, adenosine injection, USP should be used with caution in the presence of these agents. The use of adenosine injection, USP in patients receiving digitalis may be rarely associated with ventricular fibrillation (see WARNINGS ). The effects of adenosine are antagonized by methylxanthines such as caffeine and theophylline. In the presence of these methylxanthines, larger doses of adenosine may be required or adenosine may not be effective. Adenosine effects are potentiated by dipyridamole. Thus, smaller doses of adenosine may be effective in the presence of dipyridamole. Carbamazepine has been reported to increase the degree of heart block produced by other agents. As the primary effect of adenosine is to decrease conduction through the A-V node, higher degrees of heart block may be produced in the presence of carbamazepine.

Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals have not been performed to evaluate the carcinogenic potential of adenosine injection, USP. Adenosine was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay. Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations. Fertility studies in animals have not been conducted with adenosine.

Pregnancy

Category C Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. As adenosine is a naturally occurring material, widely dispersed throughout the body, no fetal effects would be anticipated. However, since it is not known whether adenosine injection, USP can cause fetal harm when administered to pregnant women, adenosine injection, USP should be used during pregnancy only if clearly needed.

Pediatric

Use No controlled studies have been conducted in pediatric patients to establish the safety and efficacy of adenosine injection, USP for the conversion of paroxysmal supraventricular tachycardia (PSVT). However, intravenous adenosine has been used for the treatment of PSVT in neonates, infants, children and adolescents (see DOSAGE AND ADMINISTRATION ).

Geriatric Use

Clinical studies of adenosine injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, adenosine injection, USP in geriatric patients should be used with caution since this population may have a diminished cardiac function, nodal dysfunction, concomitant diseases or drug therapy that may alter hemodynamic function and produce severe bradycardia or AV block.

INTERACTIONS Methylxanthines interfere with the activity of adenosine injection ( 7.1 , 10 ) Nucleoside transport inhibitors such as dipyridamole can increase the activity of adenosine injection ( 7.1 )

7.1 Effects of Other Drugs on Adenosine Injection The vasoactive effects of adenosine are inhibited by adenosine receptor antagonists, (such as methylxanthines (e.g., caffeine, aminophylline, and theophylline). The safety and efficacy of adenosine injection in the presence of these agents has not been systematically evaluated <span class="opacity-50 text-xs">[see Overdosage (10) ]</span> . The vasoactive effects of adenosine injection are potentiated by nucleoside transport inhibitors such as dipyridamole. The safety and efficacy of adenosine in the presence of dipyridamole has not been systematically evaluated. Whenever possible, drugs that might inhibit or augment the effects of adenosine should be withheld for at least five half-lives prior to the use of adenosine injection.

7.2 Effects of Adenosine Injection on Other Drugs Adenosine injection has been given with other cardioactive drugs (such as beta adrenergic blocking agents, cardiac glycosides, and calcium channel blockers) without apparent adverse interactions, but its effectiveness with these agents has not been systematically evaluated. Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, adenosine injection should be used with caution in the presence of these agents <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> .

ACTIVE INGREDIENTS: Adenosinum Triphosphoricum Dinatrum 6X, Cinnamic Acid 6X, 8X, 10X, 30X, 200X, Colibacillinum Cum Natrum Muriaticum 15X, 30X, 100X, 200X, Dysentery Bacillus 15C, Echinacea (Angustifolia) 15X, 30X, 100X, 200X, Enterococcus Faecalis 13C, Helicobacter Pylori 15X, 30X, 100X, 200X, Legionella Pneumophila 14C, 30C, 100C, 200C, Listeria Monocytogenes 14C, 30C, 100C, 200C, Malicum Acidum 6X, Mycoplasma Pneumoniae 15X, 30X, 100X, 200X, Natrum Oxalaceticum 6X, Oroticum Acidum 6X, Petroselinum Sativum 6X, 8X, 10X, 30X, 200X, Pneumococcinum 13C, 15C, 17C, 30C, 100C, 200C, Proteus (Mirabilis) 15X, 30X, 100X, 200X, Proteus (Morgani) 30C, Proteus (Vulgaris) 15X, 30X, 100X, 200X, Pseudomonas Aeruginosa 15X, 30X, 100X, 200X, Riboflavinum 6X, Salmonella Typhi Nosode 17X, 30X, 100X, 200X, Shigella Sonnei 15C, Streptococcus Agalactiae 14C, Streptococcus Bovis 32C, Streptococcus Dysgalactiae 15C, Streptococcus Mutans 13C, Streptococcus Uberis 32C, Streptococcus Viridans 38C.

Hamamelis Virginiana (Witch Hazel)

Water Water Dipropylene Glycol

Glycereth-26 Glycerin Niacinamide 1,2-Hexanediol Camellia Sinensis Leaf Extract Bambusa Vulgaris Extract Olea Europaea (Olive)

Fruit Extract Melaleuca

Alternifolia (Tea Tree)

Extract Tremella

Fuciformis (Mushroom)

Extract Portulaca Oleracea Extract Nelumbo

Nucifera Flower Extract Rosmarinus Officinalis (Rosemary)

Leaf Extract Chamomilla

Recutita (Matricaria)

Flower Extract Centella Asiatica Extract

Salvia Officinalis (Sage)

Leaf Extract Salix

Alba (Willow)

Bark

Extract PVM/MA Copolymer PEG-60 Hydrogenated Castor Oil Arginine Carbomer Allantoin Trehalose Hydroxyethylcellulose Adenosine Xanthan Gum Glyceryl Acrylate/Acrylic Acid Copolymer Hydrogenated Lecithin Polyglyceryl-10 Stearate Butylene Glycol Panthenol Sodium Ascorbyl Phosphate Tocopheryl Acetate Sodium Hyaluronate Glyceryl Linolenate Glyceryl Arachidonate Retinyl Palmitate Biotin Thiamine HCl Folic Acid Pyridoxine Cyanocobalamin Caprylyl Glycol Ethylhexylglycerin Disodium EDTA Fragrance CI 19140 CI 15985 Hamamelis Virginiana (Witch Hazel)

Water Water Dipropylene Glycol

Glycereth-26 Glycerin Niacinamide 1,2-Hexanediol Camellia Sinensis Leaf Extract Bambusa Vulgaris Extract Olea Europaea (Olive)

Fruit Extract Melaleuca

Alternifolia (Tea Tree)

Extract Tremella

Fuciformis (Mushroom)

Extract Portulaca Oleracea Extract Nelumbo

Nucifera Flower Extract Rosmarinus Officinalis (Rosemary)

Leaf Extract Chamomilla

Recutita (Matricaria)

Flower Extract Centella Asiatica Extract

Salvia Officinalis (Sage)

Leaf Extract Salix

Alba (Willow)

Bark

Extract PVM/MA Copolymer PEG-60 Hydrogenated Castor Oil Arginine Carbomer Allantoin Trehalose Hydroxyethylcellulose Adenosine Xanthan Gum Glyceryl Acrylate/Acrylic Acid Copolymer Hydrogenated Lecithin Polyglyceryl-10 Stearate Butylene Glycol Panthenol Sodium Ascorbyl Phosphate Tocopheryl Acetate Sodium Hyaluronate Glyceryl Linolenate Glyceryl Arachidonate Retinyl Palmitate Biotin Thiamine HCl Folic Acid Pyridoxine Cyanocobalamin Caprylyl Glycol Ethylhexylglycerin Disodium EDTA Fragrance CI 19140 CI 15985