atropine/pralidoxime

Atropine/pralidoxime is a combination of two medications used as antidotes to poisoning from organophosphorus nerve agents or insecticides. The two medications are contained in two separate chambers in an autoinjector, administered intramuscularly to deliver the two drugs sequentially, upon exposure to organophosphate poisoning.

Atropine/pralidoxime is approved by the FDA for self or buddy-administration by military personnel who have been exposed to nerve agents such as sarin, soman, tabun or VX, and administration by trained emergency medical services personnel to treat organophosphate poisoning from insecticides, in adults, and pediatric patients weighing more than 41 kg.

Organophosphorus nerve agents and insecticides block the activity of acetylcholinesterase, an enzyme that breaks down acetylcholine, leading to excessive accumulation of acetylcholine. Acetylcholine is a chemical (neurotransmitter) in the central and peripheral nervous system, which regulates muscle contractions and glandular secretions by stimulating two types of receptors known as muscarinic and nicotinic receptors.

Acetylcholine is normally broken down by acetylcholinesterase after completion of neurotransmission, preventing its accumulation. Acetylcholine accumulation disrupts the normal functioning of multiple organs in the body, including stimulation of excessive body secretions, skeletal muscle contractions, abnormal slowing down of heart contractions, and respiratory paralysis, which can lead to death if not promptly treated.

The two medications atropine and pralidoxime counter the effects acetylcholine accumulation from organophosphorus poisoning in the following ways:

• Atropine: Atropine binds to muscarinic receptors and prevent their stimulation by acetylcholine, reducing the symptoms caused by overstimulation of the parasympathetic nervous system. Atropine increases heart contractions, reduces oral and respiratory secretions, and dilates the airway, making breathing easier. Atropine may also block acetylcholine activity in the respiratory center in the brain and reduce acetylcholine-induced respiratory paralysis.
• Pralidoxime: Pralidoxime reactivates the enzyme acetylcholinesterase which has been deactivated by the organophosphorus agent, enabling the breakdown of acetylcholine and reduction in its levels and activity. Destruction of the accumulated acetylcholine restores normal function at the neuromuscular junctions, including activation of the paralyzed respiratory muscles.

• Atropine can cause adverse cardiac reactions including rapid heart rate (tachycardia), irregular heart rhythm (arrhythmias) and heart attack (myocardial infarction). Atropine should be used with caution in patients who have had a recent heart attack, known cardiovascular disease or cardiac conduction disorders.
• Atropine inhibits sweating which can increase the body temperature to dangerous levels and cause heat injury in patients exposed to exercise and/or warm environment.
• Use atropine with caution in patients:
  • At risk for acute glaucoma, a condition that damages the optic nerve
  • With bladder outflow obstruction, because of the risk for urinary retention
  • Who have thickening of the opening from stomach to the intestines (pyloric stenosis), because of the risk for complete pyloric obstruction
  • With myasthenia gravis, may precipitate a myasthenic crisis
• Atropine can cause inspiration of bronchial secretions and formation of sticky plugs in patients with chronic lung disease, which can block the airway. Monitor respiratory status in patients with chronic lung disease after administration of atropine.
• Use with caution in patients with impaired kidney or liver function.
• Older individuals and young children are more susceptible to the anticholinergic effects of atropine.
• Antidote administration is only for initial management of poisoning. Additional medical care may be required. Administration of additional doses of atropine/pralidoxime in asymptomatic individuals can result in toxicity.
• Atropine effects may occur earlier when administered with pralidoxime, than with atropine as a single agent. Monitor the patient closely if administering subsequent doses.
• Pralidoxime does not reactivate acetylcholinesterase inactivated by all organophosphorus nerve agents, for example, soman nerve gas. Pralidoxime cannot reactivate inactivated acetylcholinesterase that has undergone further chemical reaction known as “aging.”

Common side effects of atropine/pralidoxime include:

• Injection site reactions including:
  • Pain
  • Muscle tightness

Atropine:

Common side effects of atropine include:

• Cardiovascular effects including:
  • Palpitations
  • Irregular heart rhythm (arrhythmia)
  • Premature ventricular contractions
  • Rapid heart rate (tachycardia)
  • Atrial flutter
  • Rapid and irregular atrial contraction (atrial fibrillation)
  • Ventricular flutter
  • Ventricular fibrillation
  • Heart attack (myocardial infarction)
  • Fainting due to reduced cardiac output (cardiac syncope)
  • Flatline (asystole)
• Flushing
• Absence of sweating and increase in body temperature
• Heat injury from high temperature
• Headache
• Dizziness
• Confusion
• Dry eyes
• Blurred vision
• Light sensitivity (photophobia)
• Acute angle closure glaucoma, a condition that damages the optic nerve
• Dry mouth
• Nausea
• Vomiting
• Constipation
• Abdominal pain
• Abdominal distention
• Swallowing difficulties (dysphagia)
• Paralysis of intestinal muscles (paralytic ileus)
• Urinary hesitancy
• Urinary retention
• Loss of libido
• Impotence
• Rashes such as:
  • Maculopapular rash
  • Petechial rash
  • Scarlatiniform rash
• Skin peeling
• Central nervous system effects with higher doses, including:
  • Restlessness
  • Fatigue
  • Delirium
  • Hallucinations
  • Movement difficulties
  • Tremor

Rare side effects of atropine include:

• Severe allergic reaction (anaphylactic reaction)
• Spasm of the voice box (laryngospasm)

Pralidoxime:

• Double vision (diplopia)
• Blurred vision
• Focusing difficulty (impaired accommodation)
• Dizziness
• Drowsiness
• Headache
• Muscle weakness
• Nausea
• Rapid heart rate (tachycardia)
• Increased systolic and diastolic blood pressure
• Rapid and deep breathing (hyperventilation)
• Dry mouth
• Vomiting
• Reduced kidney function
• Reduced sweating
• Rash
• Dry skin
• Manic behavior after recovery of consciousness
• Transient elevation of liver enzymes ALT and AST
• Transient elevation of creatine kinase

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Intramuscular (IM) Autoinjector

• Atropine (2.1 mg/0.7 mL) plus pralidoxime chloride (600 mg/2 mL) in 2 separate chambers; when activated, sequentially administers both drugs intramuscularly (IM) through a single needle

Adult and Pediatric:

Organophosphate Poisoning

• Children weighing 41 kg or less: Safety and efficacy not established
• Indicated for treatment of poisoning by organophosphorus nerve agents as well as organophosphorus insecticides in adults and pediatric patients weighing more than 41 kg (90 pounds)
• Older individuals may be more susceptible to atropine effects
• 2.1 mg atropine/0.7 mL plus 600 mg pralidoxime/2 mL IM
• Maximum dose: Not to exceed 3 injections unless medical care support available
• 3 autoinjectors should be available for use in each patient (including healthcare providers) at risk for organophosphorus poisoning; use 1 for mild symptoms plus 2 more for severe symptoms

Mild symptoms

• Two or more mild symptoms: 1 injection IM; if after 10-15 minutes there are no severe symptoms experienced, no further injections are necessary
• Additional doses: If, at any time following the first injection, the patient develops any of the severe symptoms, administer 2 additional IM injections in rapid succession
• Mild symptoms: Bradycardia, chest tightness, breathing difficulties, blurred vision, increased salivation (e.g., sudden drooling), miosis, nausea or vomiting, runny nose, stomach cramps (acute onset), salivation, teary eyes, wheezing/coughing, tremors/muscular twitching, airway secretions increased

Severe symptoms

• Any severe symptom listed below: 3 injections IM in rapid succession
• Severe symptoms: Confused/strange behavior, involuntary urination/defecation, muscular twitching/generalized weakness (severe), severe breathing difficulties or copious secretion from lung or airway, convulsions, unconsciousness

Dosing Modifications

Renal impairment

• Pralidoxime can cause decreased renal function
• Patients with severe renal impairment may require less frequent doses after initial dose

Hepatic impairment

• Patients with severe hepatic impairment may require less frequent doses after initial dose

Dosing Considerations

• Three autoinjectors should be available for use in each patient (including healthcare providers) at risk for organophosphorus poisoning; one (1) for mild symptoms plus two (2) more for severe symptoms; note that individuals may not have all symptoms included under mild or severe symptom category
• Only administer drug to patients experiencing symptoms of organophosphorus poisoning in a situation where exposure is known or suspected; autoinjector is intended as an initial treatment of symptoms of organophosphorus nerve agent or insecticide poisonings as soon as symptoms appear; definitive medical care should be sought immediately
• The autoinjector should be administered by healthcare providers with adequate training in recognition and treatment of nerve agent or insecticide intoxication
• Close supervision of all treated patients is indicated for at least 48 to 72 hours

Overdose

• Atropine overdose can cause flushing, dry skin and mucous membranes, rapid heart rate, dilated pupils with poor response to light, blurred vision, and fever that can be dangerously high. Other symptoms include movement difficulties, disorientation, hallucinations, delirium, confusion, agitation, coma, and central depression that may last 48 hours or longer. Severe overdose can result in respiratory depression, coma, circulatory collapse, and death.
• Pralidoxime overdose can cause symptoms that may be difficult to differentiate from those caused by organophosphorus poisoning. Pralidoxime overdose symptoms may include dizziness, blurred vision, double vision, headache, nausea, impaired eye focusing, rapid heart rate, and transient high blood pressure that may last several hours.
• Atropine/pralidoxime overdose may be treated with supportive therapies including:
  • Ice bags and/or a hypothermia blanket to reduce fever
  • Darkened room to manage photophobia
  • Catheterization in case of urinary retention and intravenous fluids to increase urine output
  • Oxygen with artificial respiration if respiratory depression is present
  • Benzodiazepine to control excitement and convulsions

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Atropine/pralidoxime has no listed severe interactions with other drugs.
• Serious interactions of atropine/pralidoxime include:
  • eluxadoline
  • glucagon
  • glucagon intranasal
  • glycopyrronium tosylate topical
  • macimorelin
  • pramlintide
  • revefenacin
  • secretin
  • umeclidinium bromide/vilanterol inhaled
• Atropine/pralidoxime has moderate interactions with at least 119 different drugs.
• Mild interactions of atropine/pralidoxime include:
  • amitriptyline
  • amoxapine
  • atenolol
  • chlorpromazine
  • clomipramine
  • desipramine
  • dimenhydrinate
  • donepezil
  • doxepin
  • galantamine

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• Atropine crosses the placenta and enters the fetal circulation. There are no adequate animal reproductive studies or data on the use of atropine, pralidoxime or the combination in pregnant women, and risk to the fetus. Antidotes to poisoning, including atropine/pralidoxime, should not be withheld from pregnant women if clearly needed, for fear of fetal harm.
• Atropine is present in breastmilk, however, it is not known if pralidoxime is excreted in breastmilk. There is no information on the effects of either drug on milk production or the breastfed infant. Decision to breastfeed should be based on the mother’s clinical need for atropine/pralidoxime, benefits of breastfeeding to the infant, and potential risk to the infant from exposure to the drug or underlying maternal condition.