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blood pressure increased by 16 ± 19 mmHg, at 15 minutes post-dose. Blood pressures remained elevated at these approximate levels through 1 hour post-dose, began to decrease at 2 hours post-dose and were near pre-dose baseline at 4 hours post-dose. Intravenous pralidoxime doses of 30-45 mg/kg can produce moderate to marked increases in diastolic and systolic blood pressure. BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION Rx Only Atropine 2.1 mg/0.7 mL Pralidoxime Chloride 600 mg/2 mL Sterile solutions for intramuscular use only FOR USE IN NERVE AGENT AND INSECTICIDE POISONING ONLY THE DUODOTE™ AUTO-INJECTOR SHOULD BE ADMINISTERED BY EMERGENCY MEDICAL SERVICES PERSONNEL WHO HAVE HAD ADEQUATE TRAINING IN THE RECOGNITION AND TREATMENT OF NERVE AGENT OR INSECTICIDE INTOXICATION. INDICATIONS AND USAGE DuoDote™ Auto-Injector is indicated for the treatment of poisoning by organophosphorus nerve agents as well as organophosphorus insecticides. DuoDote™ Auto-Injector should be administered by emergency medical services personnel who have had adequate training in the recognition and treatment of nerve agent or insecticide intoxication. DuoDote™ Auto-Injector is intended as an initial treatment of the symptoms of organophosphorus insecticide or nerve agent poisonings; definitive medical care should be sought immediately. DuoDote™ Auto-Injector should be administered as soon as symptoms of organophosphorus poisoning appear (eg, usually tearing, excessive oral secretions, sneezing, muscle fasciculations). CONTRAINDICATIONS In the presence of life-threatening poisoning by organophosphorus nerve agents or insecticides, there are no absolute contraindications to the use of DuoDote™ Auto-Injector. WARNINGS CAUTION! INDIVIDUALS SHOULD NOT RELY SOLELY UPON ATROPINE AND PRALIDOXIME TO PROVIDE COMPLETE PROTECTION FROM CHEMICAL NERVE AGENTS AND INSECTICIDE POISONING. PRIMARY PROTECTION AGAINST EXPOSURE TO CHEMICAL NERVE AGENTS AND INSECTICIDE POISONING IS THE WEARING OF PROTECTIVE GARMENTS INCLUDING MASKS DESIGNED SPECIFICALLY FOR THIS USE. EVACUATION AND DECONTAMINATION PROCEDURES SHOULD BE UNDERTAKEN AS SOON AS POSSIBLE. MEDICAL PERSONNEL ASSISTING EVACUATED VICTIMS OF NERVE AGENT POISONING SHOULD AVOID CONTAMINATING THEMSELVES BY EXPOSURE TO THE VICTIM’S CLOTHING. When symptoms of poisoning are not severe, DuoDote™ Auto-Injector should be used with extreme caution in people with heart disease, arrhythmias, recent myocardial infarction, severe narrow angle glaucoma, pyloric stenosis, prostatic hypertrophy, significant renal insufficiency, chronic pulmonary disease, or hypersensitivity to any component of the product. Organophosphorus nerve agent poisoning often causes bradycardia but can be associated with a heart rate in the low, high, or normal range. Atropine increases heart rate and alleviates the bradycardia. In patients with a recent myocardial infarction and/or severe coronary artery disease, there is a possibility that atropine-induced tachycardia may cause ischemia, extend or initiate myocardial infarcts, and stimulate ventricular ectopy and fibrillation. In patients without cardiac disease, atropine administration is associated with the rare occurrence of ventricular ectopy or ventricular tachycardia. Conventional systemic doses may precipitate acute glaucoma in susceptible individuals, convert partial pyloric stenosis into complete pyloric obstruction, precipitate urinary retention in individuals with prostatic hypertrophy, or cause inspiration of bronchial secretions and formation of dangerous viscid plugs in individuals with chronic lung disease. More than 1 dose of DuoDote™ Auto-Injector, to a maximum of 3 doses, may be necessary initially when symptoms are severe. No more than 3 doses should be administered unless definitive medical care (eg, hospitalization, respiratory support) is available. Severe difficulty in breathing after organophosphorus poisoning requires artificial respiration in addition to the use of DuoDote™ Auto-Injector. A potential hazardous effect of atropine is inhibition of sweating, which in a warm environment or with exercise, can lead to hyperthermia and heat injury. The elderly and children may be more susceptible to the effects of atropine. PRECAUTIONS General: The desperate condition of the organophosphorus-poisoned individual will generally mask such minor signs and symptoms of atropine and pralidoxime treatment as have been noted in normal subjects. Because pralidoxime is excreted in the urine, a decrease in renal function will result in increased blood levels of the drug. DuoDote™ Auto-Injector temporarily increases blood pressure, a known effect of pralidoxime. In a study of 24 healthy young adults administered a single dose of atropine and pralidoxime auto-injector intramuscularly (approximately 9 mg/kg pralidoxime chloride), diastolic blood pressure increased from baseline by 11 ± 14 mmHg (mean ± SD), and systolic Laboratory Tests: If organophosphorus poisoning is known or suspected, treatment should be instituted without waiting for confirmation of the diagnosis by laboratory tests. Red blood cell and plasma cholinesterase, and urinary paranitrophenol measurements (in the case of parathion exposure) may be helpful in confirming the diagnosis and following the course of the illness. However, miosis, rhinorrhea, and/or airway symptoms due to nerve agent vapor exposure may occur with normal cholinesterase levels. Also, normal red blood cell and plasma cholinesterase values vary widely by ethnic group, age, and whether the person is pregnant. A reduction in red blood cell cholinesterase concentration to below 50% of normal is strongly suggestive of organophosphorus ester poisoning. Drug Interactions: When atropine and pralidoxime are used together, pralidoxime may potentiate the effect of atropine. When used in combination, signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of atropine and pralidoxime. • Barbiturates are potentiated by the anticholinesterases; therefore, barbiturates should be used cautiously in the treatment of convulsions. • Morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in treating personnel with organophosphorus poisoning. • Succinylcholine and mivacurium are metabolized by cholinesterases. Since pralidoxime reactivates cholinesterases, use of pralidoxime in organophosphorus poisoning may accelerate reversal of the neuromuscular blocking effects of succinylcholine and mivacurium. Drug-drug interaction potential involving cytochrome P450 isozymes has not been studied. Carcinogenesis, Mutagenesis, Impairment of Fertility: DuoDote™ Auto-Injector is indicated for short-term emergency use only, and no adequate studies regarding the potential of atropine or pralidoxime chloride for carcinogenesis or mutagenesis have been conducted. Impairment of Fertility: In studies in which male rats were orally administered atropine (62.5 to 125 mg/kg) for one week prior to mating and throughout a 5-day mating period with untreated females, a dose-related decrease in fertility was observed. A no-effect dose for male reproductive toxicity was not established. The low-effect dose was 290 times (on a mg/m2 basis) the dose of atropine in a single application of DuoDote™ Auto-Injector (2.1 mg). Fertility studies of atropine in females or of pralidoxime in males or females have not been conducted. Pregnancy: Pregnancy Category C: Adequate animal reproduction studies have not been conducted with atropine, pralidoxime, or the combination. It is not known whether pralidoxime or atropine can cause fetal harm when administered to a pregnant woman or if they can affect reproductive capacity. Atropine readily crosses the placental barrier and enters the fetal circulation. DuoDote™ Auto-Injector should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Atropine has been reported to be excreted in human milk. It is not known whether pralidoxime is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DuoDote™ Auto-Injector is administered to a nursing woman. Pediatric Use: Safety and effectiveness of DuoDote™ Auto-Injector in pediatric patients have not been established. ADVERSE REACTIONS Muscle tightness and sometimes pain may occur at the injection site. Atropine The most common side effects of atropine can be attributed to its antimuscarinic action. These include dryness of the mouth, blurred vision, dry eyes, photophobia, confusion, headache, dizziness, tachycardia, palpitations, flushing, urinary hesitancy or retention, constipation, abdominal pain, abdominal distention, nausea and vomiting, loss of libido, and impotence. Anhidrosis may produce heat intolerance and impairment of temperature regulation in a hot environment. Dysphagia, paralytic ileus, and acute angle closure glaucoma, maculopapular rash, petechial rash, and scarletiniform rash have also been reported. Larger or toxic doses may produce such central effects as restlessness, tremor, fatigue, locomotor difficulties, delirium followed by hallucinations, depression, and, ultimately medullary paralysis and death. Large doses can also lead to circulatory collapse. In such cases, blood pressure declines and death due to respiratory failure may ensue following paralysis and coma. Cardiovascular adverse events reported in the literature for atropine include, but are not limited to, sinus tachycardia, palpitations, premature ventricular contractions, atrial flutter, atrial fibrillation, ventricular flutter, ventricular fibrillation, cardiac syncope, asystole, and myocardial infarction. (See PRECAUTIONS.) Hypersensitivity reactions will occasionally occur, are usually seen as skin rashes, and may progress to exfoliation. Anaphylactic reaction and laryngospasm are rare. Pralidoxime Chloride Pralidoxime can cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure, muscular weakness, dry mouth, emesis, rash, dry skin, hyperventilation, decreased renal function, and decreased sweating when given parenterally to normal volunteers who have not been exposed to anticholinesterase poisons. In several cases of organophosphorus poisoning, excitement and manic behavior have occurred immediately following recovery of consciousness, in either the presence or absence of pralidoxime administration. However, similar behavior has not been reported in subjects given pralidoxime in the absence of organophosphorus poisoning. Elevations in SGOT and/or SGPT enzyme levels were observed in 1 of 6 normal volunteers given 1200 mg of pralidoxime intramuscularly, and in 4 of 6 volunteers given 1800 mg intramuscularly. Levels returned to normal in about 2 weeks. Transient elevations in creatine kinase were observed in all normal volunteers given the drug. Atropine and Pralidoxime Chloride When atropine and pralidoxime are used together, the signs of atropinization may occur earlier than might be expected when atropine is used alone. OVERDOSAGE Symptoms: Atropine Manifestations of atropine overdose are dose-related and include flushing, dry skin and mucous membranes, tachycardia, widely dilated pupils that are poorly responsive to light, blurred vision, and fever (which can sometimes be dangerously elevated). Locomotor difficulties, disorientation, hallucinations, delirium, confusion, agitation, coma, and central depression can occur and may last 48 hours or longer. In instances of severe atropine intoxication, respiratory depression, coma, circulatory collapse, and death may occur. The fatal dose of atropine is unknown. In the treatment of organophosphorus poisoning, doses as high as 1000 mg have been given. The few deaths in adults reported in the literature were generally seen using typical clinical doses of atropine often in the setting of bradycardia associated with an acute myocardial infarction, or with larger doses, due to overheating in a setting of vigorous physical activity in a hot environment. Pralidoxime It may be difficult to differentiate some of the side effects due to pralidoxime from those due to organophosphorus poisoning. Symptoms of pralidoxime overdose may include: dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, and slight tachycardia. Transient hypertension due to pralidoxime may last several hours. Treatment: For atropine overdose, supportive treatment should be administered. If respiration is depressed, artificial respiration with oxygen is necessary. Ice bags, a hypothermia blanket, or other methods of cooling may be required to reduce atropine-induced fever, especially in children. Catheterization may be necessary if urinary retention occurs. Since atropine elimination takes place through the kidney, urinary output must be maintained and increased if possible; intravenous fluids may be indicated. Because of atropine-induced photophobia, the room should be darkened. A short-acting barbiturate or diazepam may be needed to control marked excitement and convulsions. However, large doses for sedation should be avoided because central depressant action may coincide with the depression occurring late in severe atropine poisoning. Central stimulants are not recommended. Physostigmine, given as an atropine antidote by slow intravenous injection of 1 to 4 mg (0.5 to 1.0 mg in children) rapidly abolishes delirium and coma caused by large doses of atropine. Since physostigmine has a short duration of action, the patient may again lapse into coma after 1 or 2 hours, and require repeated doses. Neostigmine, pilocarpine, and methacholine are of little benefit, since they do not penetrate the blood-brain barrier. Pralidoxime-induced hypertension has been treated by administering phentolamine 5 mg intravenously, repeated if necessary due to phentolamine’s short duration of action. In the absence of substantial clinical data regarding use of phentolamine to treat pralidoxime-induced hypertension, consider slow infusion to avoid precipitous corrections in blood pressure. © 2010 Meridian Medical Technologies™, Inc., a subsidiary of King Pharmaceuticals® , Inc. Manufactured by: Meridian Medical Technologies™, Inc. Columbia, MD 21046 DuoDote and the DuoDote Logo are registered trademarks of Meridian Medical Technologies™, Inc. MMT 5173 02/2010