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Adenosine
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. Adenocard® (adenosine) is a sterile
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
5.5 and 7.5.
Mechanism of Action Adenocard (adenosine) slows conduction time through the A-V node, can interrupt the reentry pathways through the A-V node, and can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-Parkinson-White Syndrome. Adenocard is antagonized competitively by methylxanthines such as caffeine and theophylline, and potentiated by blockers of nucleoside transport such as dipyridamole. Adenocard is not blocked by atropine. Hemodynamics The usual intravenous bolus dose of 6 or 12 mg Adenocard (adenosine) will have no systemic hemodynamic effects. When larger doses are given by infusion, adenosine decreases blood pressure by decreasing peripheral resistance. Pharmacokinetics Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical. Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Since adenosine kinase has a lower Km and Vmax than adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. While extracellular adenosine is primarily cleared by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ectoform of adenosine deaminase. As Adenocard requires no hepatic or renal function for its activation or inactivation, hepatic and renal failure would not be expected to alter its effectiveness or tolerability. Clinical Trial Results In controlled studies in the United States, bolus doses of 3, 6, 9, and 12 mg were studied. A cumulative 60% of patients with paroxysmal supraventricular tachycardia had converted to normal sinus rhythm within one minute after an intravenous bolus dose of 6 mg Adenocard (some converted on 3 mg and failures were given 6 mg), and a cumulative 92% converted after a bolus dose of 12 mg. Seven to sixteen percent of patients converted after 1—4 placebo bolus injections. Similar responses were seen in a variety of patient subsets, including those using or not using digoxin, those with Wolff-Parkinson-White Syndrome, males, females, blacks, Caucasians, and Hispanics. Adenosine is not effective in converting rhythms other than PSVT
such as atrial flutter, atrial
fibrillation, or ventricular
tachycardia, to normal sinus
rhythm. To date, such patients have not had adverse consequences following
administration of adenosine.
Intravenous Adenocard (adenosine) 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 Adenocard administration. It is important to be sure the Adenocard solution
actually reaches the systemic circulation
(see
For rapid bolus intravenous use only. Adenocard (adenosine) Injection 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 IV line, it should be given as close to the patient as possible and followed by a rapid saline flush. The dose recommendation is based on clinical studies with peripheral venous bolus dosing. Central venous (CVP or other) administration of Adenocard 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—2 second period). Repeat administration: If the first dose does not result in elimination of the supraventricular tachycardia within 1—2 minutes, 12 mg should be given as a rapid intravenous bolus. This 12 mg dose may be repeated a second time if required. Doses greater than 12 mg are not recommended. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. HOW SUPPLIED Adenocard® (adenosine) Injection is supplied as a sterile solution in normal saline. Store at controlled room temperature 15°—30°C (59°—86°F). 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. Contains no preservatives. Discard unused portion. CAUTION: Federal wlaw prohibits
dispensing without prescription.
The following reactions were reported with intravenous Adenocard (adenosine) used in controlled U.S. clinical trials. The placebo group had a less than 1% rate of all of these reactions. Cardiovascular: Facial flushing (18%), headache (2%), sweating, palpitations, chest pain, hypotension (less than 1%). Respiratory: Shortness of breath / dyspnea (12%), chest pressure (7%), hyperventilation, head pressure (less than 1%). Central Nervous System: Lightheadedness (2%), dizziness, tingling in arms, numbness (1%), apprehension, blurred vision, burning sensation, heaviness in arms, neck and back pain (less than 1%). Gastrointestinal: Nausea (3%), metallic taste, tightness in throat, pressure in groin (less than 1%). In post-market clinical experience with Adenocard, cases of prolonged asystole, ventricular tachycardia, ventricular fibrillation, transient increase in blood pressure, bradycardia, hypotension, atrial fibrillation, and bronchospasm, in association with Adenocard use, have been reported.
Intravenous Adenocard (adenosine) 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 Adenocard (see WARNINGS). Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, Adenocard should be used with caution in the presence of these agents. The use of Adenocard 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.
Heart Block Adenocard (adenosine) exerts its effect by decreasing conduction through the A-V node and may produce a short lasting first-, second-, or third-degree heart block. In extreme cases, transient asystole may result (one case has been reported in a patient with atrial flutter who was receiving carbamazepine). Appropriate therapy should be instituted as needed. Patients who develop high-level block on one dose of Adenocard should not be given additional doses. Because of the very short half-life of adenosine, these effects are generally self-limiting. Rarely, ventricular fibrillation has been reported following Adenocard administration, including both resuscitated and fatal events. In most instances, these cases were associated with the concomitant use of digoxin, and less frequently with digoxin and verapamil. Although no causal relationship or drug-drug interaction has been established, Adenocard should be used with caution in patients receiving digoxin or digoxin and verapamil in combination. Appropriate resuscitative measures should be available. Arrhythmias at Time of Conversion At the time of conversion to normal sinus rhythm, a variety of new rhythms may appear on the electrocardiogram. They generally last only a few seconds without intervention, and may take the form of premature ventricular contractions, atrial premature contractions, sinus bradycardia, sinus tachycardia, skipped beats, and varying degrees of A-V nodal block. Such findings were seen in 55% of patients. Bronchoconstriction Adenocard (adenosine) is a respiratory stimulant (probably through activation of carotid body chemoreceptors) and intravenous administration in man has been shown to increase minute ventilation (ye) and reduce arterial PCO2 causing respiratory alkalosis. Adenosine administered by inhalation has been reported to cause bronchoconstriction in asthmatic patients, presumably due to mast cell degranulation and histamine release.These effects have not been observed in normal subjects. Adenocard has been administered to a limited number of patients with asthma and mild to moderate exacerbation of their symptoms has been reported. Respiratory compromise has occurred during adenosine infusion in patients with obstructive pulmonary disease. Adenocard should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis, etc.) and should be avoided in patients with bronchoconstriction or bronchospasm (e.g., asthma). Adenocard should be discontinued in any patient who develops severe respiratory difficulties.
Drug Interactions See DRUG INTERACTIONS section. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals have not been performed to evaluate the carcinogenic potential of Adenocard (adenosine). 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. In rats and mice, adenosine administered intraperitoneally once a day for five days at 50, 100, and 150 mg/kg [10-30(rats) and 5-15 (mice) times human dosage on a mg/M2 basis] caused decreased spermatogenesis and increased numbers of abnormal sperm, a reflection of the ability of adenosine to produce chromosomal damage. 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 Adenocard can cause fetal harm when administered to pregnant women, Adenocard should be used during pregnancy only if clearly needed. Pediatrics No controlled studies have been conducted in pediatric
patients.
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