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DALFAMPRIDINE/4-AMINOPYRIDINE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dalfampridine (chemical name of 4-aminopyridine) and amifampridine (3,4-diaminopyridine), are potassium channel blockers. Dalfampridine is FDA-approved to help improve walking in multiple sclerosis patients, as demonstrated by an increase in walking speed. Amifampridine is indicated for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults.

Specific Substances

    A) AMIFAMPRIDINE
    1) 3,4-Diaminopyridine
    2) CAS 54-96-6
    DALFAMPRIDINE
    1) 4-Aminopyridine
    2) 4-AP
    3) Fampridine
    4) Avitrol
    5) CAS 504-24-5

    1.2.1) MOLECULAR FORMULA
    1) C5-H6-N2

Available Forms Sources

    A) FORMS
    1) Dalfampridine is available as 10 mg extended-release tablets (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    2) Amifampridine is available as 10 mg scored tablets (Prod Info FIRDAPSE oral tablets, 2012).
    B) USES
    1) Dalfampridine is FDA-approved to help improve walking in patients with multiple sclerosis (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    2) 4-aminopyridine is also an acutely toxic pesticide developed by Phillips Petroleum and marketed in 1963 as an avicide (bird repellent) under the name Avitrol.
    a) It is marketed as a poison bait containing corn, wheat, sorghum or peanut butter in an 0.03% to 1.0% concentration.
    3) Fampridine has been used investigationally as a specific treatment of the presynaptic lesion in Eaton-Lambert Syndrome, as an antagonist for blockade caused by botulinum toxin or pancuronium bromide, and in the treatment of multiple sclerosis (Stefoski et al, 1987).
    4) Amifampridine is indicated for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults (Prod Info FIRDAPSE oral tablets, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Dalfampridine (4-aminopyridine) is indicated for the improvement in walking in multiple sclerosis patients. Amifampridine is used for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults.
    B) PHARMACOLOGY: Dalfampridine is a broad spectrum potassium channel blocker; however, it is unknown how it exerts its therapeutic effect. Animal studies demonstrated an increase in conduction of action potentials in demyelinated axons through inhibition of potassium channels. Dalfampridine neither prolongs the QTc interval nor has any meaningful effect on the QRS duration.
    C) EPIDEMIOLOGY: Overdose ingestions have occasionally occurred; however, severe toxicity is rare.
    D) WITH THERAPEUTIC USE
    1) Insomnia, dizziness, headache, paresthesia, seizures, urinary tract infections, nausea, vomiting, abdominal pain, and back pain have been reported following therapeutic administration of 4-aminopyridine.
    E) WITH POISONING/EXPOSURE
    1) DALFAMPRIDINE: Altered mental status, seizures, weakness, memory loss, hypophonic speech, choreoathetoid movements, diaphoresis, vomiting, and metabolic acidosis have occurred following overdose ingestions of 4-aminopyridine.
    2) AMIFAMPRIDINE: Nausea, vomiting, paresthesias, seizures, and cardiac complications, including supraventricular tachycardia and cardiac arrest, have been reported in one patient following a 6-fold overdose ingestion over 6 days.
    0.2.20) REPRODUCTIVE
    A) Dalfampridine has been classified as FDA pregnancy category C. In animal studies, decreased offspring viability and growth were observed at doses similar to the recommended human dose throughout pregnancy and lactation periods in rats. In male and female rats, there were no adverse effects on fertility following exposure to dalfampridine.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of dalfampridine in humans.

Laboratory Monitoring

    A) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise indicated.
    B) 4-aminopyridine levels are not clinically useful.
    C) Quantitative analysis for 4-aminopyridine is expected to be available only at very sophisticated laboratories.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Most 4-aminopyridine exposures require supportive care only.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treat seizures with benzodiazepines. Status epilepticus should be treated with high-dose benzodiazepines, followed by propofol and/or barbiturates l if benzodiazepines are ineffective. Manage airway in patients with recurrent seizures.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal is not recommended due to the potential for seizures.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected.
    D) AIRWAY MANAGEMENT
    1) Airway management may be necessary for severe refractory seizures.
    E) ANTIDOTE
    1) None.
    F) SEIZURE
    1) Administer IV benzodiazepines; add propofol and/or barbiturates if seizures recur or persist.
    G) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are unlikely to be effective following dalfampridine (4-aminopyridine) overdose ingestions due to its large volume of distribution (2.6 L/kg).
    H) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Patients with neurologic toxicity should be treated and observed until symptoms resolve.
    2) ADMISSION CRITERIA: Patients demonstrating seizure activity or other persistent neurotoxicity should be admitted.
    3) CONSULT CRITERIA: Consult a medical toxicologist or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) When managing a suspected dalfampridine (4-aminopyridine) overdose, the treating physician should be aware of the possibility of multi-drug involvement.
    J) PHARMACOKINETICS
    1) Dalfampridine is rapidly and completely absorbed with a relative bioavailability of 96%. It is largely unbound to plasma proteins, with an apparent volume of distribution of 2.6 L/kg. Dalfampridine is primarily excreted unchanged (90.3%) in the urine, and its elimination half-life is 5.2 to 6.5 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other drugs that can cause seizures (e.g. isoniazid, bupropion, sympathomimetics).
    0.4.3) INHALATION EXPOSURE
    A) Move patient to fresh air. Monitor for respiratory distress and administer oxygen and assist ventilation as required. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, and pneumonitis. Treat bronchospasm with inhaled beta2-agonist and oral or parenteral corticosteroids.
    0.4.4) EYE EXPOSURE
    A) Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. Further evaluation may be necessary if irritation, pain, swelling, lacrimation, or photophobia persist.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Remove contaminated clothing and wash exposed area thoroughly with soap and water.

Range Of Toxicity

    A) TOXICITY: DALFAMPRIDINE: Ingestion of 0.6 mg/kg may produce toxic signs and symptoms which require hospitalization. In the clinical setting, 1 mg/kg administered IV in postoperative patients has resulted in restlessness, confusion (seizures) and central nervous system excitation during the recovery period. Ingestion of 90 to 125 mg caused status epilepticus in adults. AMIFAMPRIDINE: Ingestion of 60 mg 6 times daily for approximately 8 days, instead of the prescribed 10 mg 6 times daily, resulted in nausea, vomiting, paresthesias, generalized seizures, dysrhythmias, and cardiac arrest.
    B) THERAPEUTIC DOSE: DALFAMPRIDINE: The maximum recommended dose of dalfampridine is 10 mg twice daily. AMIFAMPRIDINE: Initially, the recommended oral dose is 15 mg/day, given in divided doses 3 or 4 times daily. The dose may be increased in 5 mg increments every 4 to 5 days, up to a maximum daily dose of 60 mg. A single dose should not exceed 20 mg.

Clinical Effects

Summary Of Exposure

    A) USES: Dalfampridine (4-aminopyridine) is indicated for the improvement in walking in multiple sclerosis patients. Amifampridine is used for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults.
    B) PHARMACOLOGY: Dalfampridine is a broad spectrum potassium channel blocker; however, it is unknown how it exerts its therapeutic effect. Animal studies demonstrated an increase in conduction of action potentials in demyelinated axons through inhibition of potassium channels. Dalfampridine neither prolongs the QTc interval nor has any meaningful effect on the QRS duration.
    C) EPIDEMIOLOGY: Overdose ingestions have occasionally occurred; however, severe toxicity is rare.
    D) WITH THERAPEUTIC USE
    1) Insomnia, dizziness, headache, paresthesia, seizures, urinary tract infections, nausea, vomiting, abdominal pain, and back pain have been reported following therapeutic administration of 4-aminopyridine.
    E) WITH POISONING/EXPOSURE
    1) DALFAMPRIDINE: Altered mental status, seizures, weakness, memory loss, hypophonic speech, choreoathetoid movements, diaphoresis, vomiting, and metabolic acidosis have occurred following overdose ingestions of 4-aminopyridine.
    2) AMIFAMPRIDINE: Nausea, vomiting, paresthesias, seizures, and cardiac complications, including supraventricular tachycardia and cardiac arrest, have been reported in one patient following a 6-fold overdose ingestion over 6 days.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) AMIFAMPRIDINE/CASE REPORT: A 65-year-old woman presented with general weakness, generalized paresthesias, nausea, vomiting, and palpitations. Her current medications included pyridostigmine 60 mg 8 times daily, domperidone 10 mg 3 times daily, and 3,4-diaminopyridine (amifampridine) 60 mg 6 times daily, all of which were continued during her hospitalization. Several hours post-admission, the patient's condition continued to deteriorate with development of severe generalized seizures, acute respiratory failure secondary to aspiration, and recurrent paroxysmal supraventricular tachycardia. With intensive supportive care, the patient's condition improved; however, 4 days post-admission, the patient had a cardiac arrest, but was successfully resuscitated. Further review of her medication list revealed that 7 days prior to admission, she had started taking 3,4-diaminopyridine 60 mg 6 times daily instead of the prescribed 10 mg 6 times daily. The medication was withdrawn for 5 days, and the patient completely recovered and was discharged 21 days post-admission (Boerma et al, 1995).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Weakness, dizziness, and disorientation have been reported in humans. Mild dizziness and gait imbalance occurred in normal subjects given total doses of 30 to 35 mg IV, which reversed 60 to 90 minutes after discontinuation (Stefoski et al, 1987).
    B) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In three placebo-controlled trials of up to 14 weeks duration in adult patients with multiple sclerosis, insomnia was reported in 9% of patients who received oral dalfampridine 10 mg twice daily (n=400) compared with 4% of patients who received placebo (n=238) (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    b) Dizziness, paresthesias, and insomnia were reported in a minority of patients in a 10-patient crossover study. The subjects received sustained-release fampridine 17.5 mg twice a day for 1 week. After withdrawal from fampridine, 2 patients reported malaise (Schwid et al, 1997).
    C) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) A 56-year-old man presented confused with unintelligible speech, a left facial droop and a possible decrease in left arm movement. He then became combative. Evaluation including cranial CT, cerebral angiography, carotid ultrasound, echocardiogram and lumbar puncture were normal. His mentation cleared about 36 hours after presentation when he admitted to taking an unknown amount of 4-aminopyridine in an attempt to treat a toothache (Johnson & Morgan, 2006).
    b) CASE REPORTS: During clinical trials, two patients with multiple sclerosis developed altered mental status following overdose ingestions of dalfampridine. The first patient ingested 60 mg (6 times the recommended dose), and the second patient ingested 40 mg. With supportive care, both patients recovered the next day without sequelae (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    D) FEELING AGITATED
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 37-year-old man with a history of chronic progressive multiple sclerosis and depression, presented with agitation, delirium, and slurred and incomprehensible speech after ingesting an unknown number of "pills". His prescribed medications included 4-aminopyridine (4-AP), paroxetine, and fingolimod. Vital signs indicated hypertension (125/104 mmHg), tachycardia (133 beats/minute), and tachypnea (30 breaths/minute). He was also diaphoretic and exhibited choreoathetoid movements and tremulousness. Despite benzodiazepine administration, the patient's agitation and delirium persisted, requiring intubation and sedation with propofol. Over the next 2 days, there was gradual improvement in his mental status, and he was extubated on hospital day 3. Following extubation, the patient exhibited paranoia, but recovered and was discharged home on hospital day 7. A 4-AP level, obtained approximately 6 hours postingestion, was 140 ng/mL (17.3 to 42.7 ng/mL), and a repeat 4-AP level, obtained 24 hours later, was 6 ng/mL. Further interview of the family indicated that the patient had been exhibiting increasing psychotic behavior following initiation of 4-AP therapy (King et al, 2012).
    E) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been observed in patients with multiple sclerosis who were treated for 9 to 14 weeks with oral dalfampridine in placebo-controlled trials. There appeared to be a dose-dependent increase in incidence, with 2 seizures (3.5%) reported at 20 mg twice daily, no seizures at 15 mg twice daily, one seizure at 10 mg twice daily (0.25%), and one seizure with placebo (0.4%). In open-label extension trials with multiple sclerosis patients (n=917), the incidence of seizures with dalfampridine 15 mg twice daily was more than 4 times higher than the incidence with 10 mg twice daily: 1.7 per 100 person-years (95% confidence interval (CI), 0.21 to 6.28) and 0.41 per 100 person-years (95% CI, 0.13 to 0.96), respectively (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    b) Seizures have been reported after intravenous fampridine in doses exceeding 0.8 to 1 mg/kg and oral doses greater than 1 to 1.5 mg/kg/day (van Diemen et al, 1992; Stefoski et al, 1991a; Wirtavuori et al, 1984; Soni & Kam, 1982a; Murray & Newsom-Davis, 1981a). Convulsions were observed in 2 patients with botulism during a continuous infusion of 0.25 mg/kg/hour that was preceded by an intravenous bolus of 0.5 mg/kg (Soni & Kam, 1982a).
    2) WITH POISONING/EXPOSURE
    a) Seizures have been reported (McEvoy et al, 1989).
    b) STATUS EPILEPTICUS CASE SERIES: Three patients (46 to 54 years of age) with secondary progressive multiple sclerosis experienced unusual sensory and behavioral symptoms that rapidly transitioned into status epilepticus (recurrent seizures without full recovery of consciousness in the intervening period or a single prolonged seizure) within minutes to hours of ingesting the first dose of 4-aminopyridine (4AP). An EEG of one patient revealed focal spike and wave activity with spread. All 3 patients had recently received a prescription for 4-AP 10 mg (one tablet) twice or three times daily, but testing of the tablets revealed that each 10 mg tablet contained between 90.1 mg to 125.6 mg of 4-AP. Following supportive care, all patients recovered from their acute illness, but were discharged with greater and chronic neurologic disability (Burton et al, 2008).
    c) CASE REPORT: A female patient with multiple sclerosis ingested 40 mg of dalfampridine on two separate instances. Following the first instance, the patient developed a complex partial seizure and, after the second 40 mg dose, she experienced confusion. With supportive care, the patient recovered the next day without sequelae (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    d) AMIFAMPRIDINE/CASE REPORT: A 65-year-old woman developed severe generalized seizures after taking amifampridine (3,4-diaminopyridine) 60 mg 6 times daily for approximately 8 days instead of the prescribed 10 mg 6 times daily (Boerma et al, 1995).
    F) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) In three placebo-controlled trials of up to 14 weeks duration in adult patients with multiple sclerosis, paresthesia was reported in 4% of patients who received oral dalfampridine 10 mg twice daily (n=400) compared with 3% of patients who received placebo (n=238) (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    b) Dizziness, paresthesias, and insomnia were reported in a minority of patients in a 10-patient crossover study. The subjects received sustained-release fampridine 17.5 mg twice a day for 1 week. After withdrawal from fampridine, 2 patients reported malaise (Schwid et al, 1997).
    c) In multiple sclerosis patients receiving up to 0.5 mg/kg/day of oral fampridine (n=70), the incidence of paresthesias, dizziness or lightheadedness, gait instability, and anxiety or restlessness was 20%, 50%, 15%, and 5%, respectively (van Diemen et al, 1992).
    d) CASE SERIES: Perioral paresthesias were noted in 10 of 12 patients, beginning 30 minutes after oral doses of 25 mg (McEvoy et al, 1989).
    1) Periorbital paresthesias occurred in all subjects given 1 to 5 mg intravenously (Stefoski et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) AMIFAMPRIDINE/CASE REPORT: Paresthesias, beginning in the feet and becoming more generalized, were reported in a 65-year-old woman who had been taking amifampridine (3,4-diaminopyridine) 60 mg 6 times daily for approximately 8 days instead of the prescribed 10 mg 6 times daily (Boerma et al, 1995).
    G) DYSTONIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 45-year-old woman, with secondary progressive multiple sclerosis, presented to the emergency department with dystonic choreoathetoid movements of all four extremities after ingesting at total of 35 mg of 4-aminopyridine divided in 3 doses and taken within a period of 10 hours. The patient had a diffuse tremor and was unresponsive to external stimuli. An arterial blood gas analysis indicated metabolic acidosis (pH 7.22). An EEG showed no evidence of epileptic activity and a brain MRI was negative for any signs of bleeding. According to the patient's current medication list, she had been taking 4-aminopyridine at a dosage regimen of 10 mg, 10 mg, and 7.5 mg daily. Following admission to ICU, all current medications were discontinued. However, rechallenge with 4-aminopyridine resulted in confusion, opisthotonus, motoric distress, and head tremor. The patient recovered following withdrawal of 4-aminopyridine (De Cauwer et al, 2009).
    H) CHOREOATHETOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Choreoathetoid movements were reported in a 37-year-old man who ingested an unknown amount of 4-aminopyridine (King et al, 2012).
    I) LIMBIC ENCEPHALITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A patient with multiple sclerosis developed a condition resembling limbic encephalitis and consisting of weakness, memory loss, a decrease in awareness, and hypophonic speech following an overdose ingestion of 300 mg of dalfampridine. An MRI revealed temporal lobe hyperintensities. Gradually, the patient's speech, language, and movement improved and, 4 months later, a repeat MRI showed no signal abnormalities. However, at the one-year follow-up, deficits in short term memory and the ability to learn new tasks continued to persist (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    J) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In three placebo-controlled trials of up to 14 weeks duration in adult patients with multiple sclerosis, dizziness was reported in 7% of patients who received oral dalfampridine 10 mg twice daily (n=400) compared with 4% of patients who received placebo (n=238). Dizziness led to discontinuation of dalfampridine in 0.5% of patients, compared with 0% taking placebo (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    b) Dizziness, paresthesias, and insomnia were reported in a minority of patients in a 10-patient crossover study. The subjects received sustained-release fampridine 17.5 mg twice a day for 1 week. After withdrawal from fampridine, 2 patients reported malaise (Schwid et al, 1997).
    c) In multiple sclerosis patients receiving up to 0.5 mg/kg/day of oral fampridine (n=70), the incidence of paresthesias, dizziness or lightheadedness, gait instability, and anxiety or restlessness was 20%, 50%, 15%, and 5%, respectively (van Diemen et al, 1992).
    K) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In three placebo-controlled trials of up to 14 weeks duration in adult patients with multiple sclerosis, headache was reported in 7% of patients who received oral dalfampridine 10 mg twice daily (n=400) compared with 4% of patients who received placebo (n=238). Headache led to discontinuation of dalfampridine in 0.5% of patients, compared with 0% taking placebo (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    L) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In three placebo-controlled trials of up to 14 weeks duration in adult patients with multiple sclerosis, asthenia was reported in 7% of patients who received oral dalfampridine 10 mg twice daily (n=400) compared with 4% of patients who received placebo (n=238) (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    M) NEUROLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) BALANCE DISORDER: In three placebo-controlled trials of up to 14 weeks duration in adult patients with multiple sclerosis, balance disorder was reported in 5% of patients who received oral dalfampridine 10 mg twice daily (n=400) compared with 1% of patients who received placebo (n=238). Balance disorder led to discontinuation of dalfampridine in 0.5% of patients, compared with 0% taking placebo (Prod Info AMPYRA(R) extended release oral tablets, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In three placebo-controlled trials of up to 14 weeks duration in adult patients with multiple sclerosis, nausea was reported in 7% of patients who received oral dalfampridine 10 mg twice daily (n=400) compared with 3% of patients who received placebo (n=238) (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    b) Nausea, vomiting, and abdominal pain have been reported in some patients treated with oral fampridine (Schwid et al, 1997; van Diemen et al, 1993a; van Diemen et al, 1992; Stefoski et al, 1991a; Davidson et al, 1988a; Murray & Newsom-Davis, 1981a) and oral amifampridine (Boerma et al, 1995). In one study involving multiple sclerosis patients treated with oral fampridine in doses up to 0.5 mg/kg/day (n=70), the incidence of nausea or vomiting was 13% (van Diemen et al, 1992).
    2) WITH POISONING/EXPOSURE
    a) Vomiting has been reported after overdose (Johnson & Morgan, 2006).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Rapid onset of disagreeable taste, immediate burning of the throat, and abdominal discomfort have been reported by humans following ingestion of 4-AP (McEvoy et al, 1989).
    b) In one study involving multiple sclerosis patients treated with oral fampridine in doses up to 0.5 mg/kg/day (n=70), the incidence of abdominal pain was 7% (van Diemen et al, 1992).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) In three placebo-controlled trials of up to 14 weeks duration in adult patients with multiple sclerosis, urinary tract infections were reported in 12% of patients who received oral dalfampridine 10 mg twice daily (n=400) compared with 8% of patients who received placebo (n=238) (Prod Info AMPYRA(R) extended release oral tablets, 2010).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Metabolic acidosis has been reported in 2 patients following 4-aminopyridine (Spyker et al, 1980).
    b) CASE REPORT: Metabolic acidosis (pH 7.22) was reported in a 45-year-old woman who ingested a total of 35 mg of 4-aminopyridine, taken in 3 doses within a 10-hour period. Acidosis in this case was likely secondary to excessive muscle activity (choreoathetosis, tremor, opisthotonus) (De Cauwer et al, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Diaphoresis has been reported after overdose (King et al, 2012; Johnson & Morgan, 2006).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In three placebo-controlled trials of up to 14 weeks duration in adult patients with multiple sclerosis, back pain was reported in 5% of patients who received oral dalfampridine 10 mg twice daily (n=400) compared with 2% of patients who received placebo (n=238) (Prod Info AMPYRA(R) extended release oral tablets, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Dalfampridine has been classified as FDA pregnancy category C. In animal studies, decreased offspring viability and growth were observed at doses similar to the recommended human dose throughout pregnancy and lactation periods in rats. In male and female rats, there were no adverse effects on fertility following exposure to dalfampridine.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    B) ANIMAL STUDIES
    1) There was a decrease in offspring viability and growth at doses similar to the maximum recommended human dose of 20 mg/day. In rat and rabbit studies, there was no evidence of developmental toxicity in either species when rats and rabbits were given maternally toxic dalfampridine doses up to 10 and 5 mg/kg/day (approximately 5 times the maximum recommended human dose on a mg/m(2) basis), respectively (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    2) RATS: There was a decrease in offspring survival and growth when rats were exposed to dalfampridine at doses of 1, 3, and 9/6 mg/kg/day (high dose reduced during week 2 of dosing) throughout the pregnancy and lactation periods. The no-effect dose for prenatal and postnatal developmental toxicity in rats (1 mg/kg) is approximately 0.5 times the maximum recommended human dose on a mg/m(2) basis (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified dalfampridine as FDA pregnancy category C (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) AMIFAMPRIDINE: It is unknown whether amifampridine is excreted in human breast milk (Prod Info FIRDAPSE oral tablets, 2012).
    2) DALFAMPRIDINE: At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    B) ANIMAL STUDIES
    1) RATS: There were no adverse effects on fertility when male and female rats were given oral dalfampridine (doses of 1, 3, and 9 mg/kg/day) prior to and throughout mating, and continuing in females up to day 13 of gestation or day 21 of lactation. The no-effect dose was similar to the maximum recommended dose on a mg/m(2) basis (Prod Info AMPYRA(R) extended release oral tablets, 2010).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of dalfampridine in humans.
    3.21.4) ANIMAL STUDIES
    A) UTERINE POLYPS
    1) A significant increase in uterine polyps was reported at the highest dose when rats were exposed to approximately 2, 6, and 18 milligrams/kilograms/day (approximately 1, 3, and 9 times the maximum recommended human dose on a body surface area basis) (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    B) LACK OF EFFECT
    1) There was no evidence of dalfampridine-related carcinogenicity in mice or rats in 2-year, dietary, carcinogenicity studies. In mice, doses of approximately 2, 12.5, and 80 mg/kg/day were associated with AUC values that were up to 18 times the plasma AUC in humans at the maximum recommended human dose of 20 mg/day (Prod Info AMPYRA(R) extended release oral tablets, 2010).

Genotoxicity

    A) There was no evidence of mutagenicity in the in vitro (bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration) and in vivo (mouse bone marrow, rat erythrocyte micronucleus) genetic toxicology assays (Prod Info AMPYRA(R) extended release oral tablets, 2010).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise indicated.
    B) 4-aminopyridine levels are not clinically useful.
    C) Quantitative analysis for 4-aminopyridine is expected to be available only at very sophisticated laboratories.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise indicated.
    2) 4-aminopyridine levels are not clinically useful.

Methods

    A) OTHER
    1) Detection or quantitation of 4-aminopyridine is expected to be available only at very sophisticated laboratories.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients demonstrating seizure activity or other persistent neurotoxicity should be admitted.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with neurologic toxicity should be treated and observed until symptoms resolve.

Monitoring

    A) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise indicated.
    B) 4-aminopyridine levels are not clinically useful.
    C) Quantitative analysis for 4-aminopyridine is expected to be available only at very sophisticated laboratories.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not recommended due to the potential for seizures.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) No specific lab work (e.g., CBC, electrolyte, urinalysis) is needed unless otherwise indicated.
    2) 4-aminopyridine levels are not clinically useful.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is unlikely to be effective following dalfampridine (4-aminopyridine) overdose ingestions due to its large volume of distribution (2.6 L/kg).

Range Of Toxicity

Summary

    A) TOXICITY: DALFAMPRIDINE: Ingestion of 0.6 mg/kg may produce toxic signs and symptoms which require hospitalization. In the clinical setting, 1 mg/kg administered IV in postoperative patients has resulted in restlessness, confusion (seizures) and central nervous system excitation during the recovery period. Ingestion of 90 to 125 mg caused status epilepticus in adults. AMIFAMPRIDINE: Ingestion of 60 mg 6 times daily for approximately 8 days, instead of the prescribed 10 mg 6 times daily, resulted in nausea, vomiting, paresthesias, generalized seizures, dysrhythmias, and cardiac arrest.
    B) THERAPEUTIC DOSE: DALFAMPRIDINE: The maximum recommended dose of dalfampridine is 10 mg twice daily. AMIFAMPRIDINE: Initially, the recommended oral dose is 15 mg/day, given in divided doses 3 or 4 times daily. The dose may be increased in 5 mg increments every 4 to 5 days, up to a maximum daily dose of 60 mg. A single dose should not exceed 20 mg.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) AMIFAMPRIDINE
    a) Initially, the recommended oral dose is 15 mg/day, given in divided doses 3 or 4 times daily. The dose may be increased in 5 mg increments every 4 to 5 days, up to a maximum daily dose of 60 mg. A single dose should not exceed 20 mg (Prod Info FIRDAPSE oral tablets, 2012).
    2) DALFAMPRIDINE
    a) The maximum recommended dose of oral dalfampridine is one 10 mg extended-release tablet twice daily, taken approximately 12 hours apart with or without food (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) AMIFAMPRIDINE
    a) Less than 18 years of age: Safety and efficacy have not been established (Prod Info FIRDAPSE oral tablets, 2012).
    2) DALFAMPRIDINE
    a) The safety and efficacy of oral dalfampridine have not been established in pediatric patients younger than 18 years of age (Prod Info AMPYRA(R) extended release oral tablets, 2010).

Maximum Tolerated Exposure

    A) DALFAMPRIDINE (4-AMINOPYRIDINE)
    1) Three patients (46 to 54 years of age) with secondary progressive multiple sclerosis experienced unusual sensory and behavioral symptoms that rapidly progressed to status epilepticus within minutes to hours of ingesting the first dose of 4-aminopyridine (4AP). An EEG of one patient revealed focal spike and wave activity with spread. All 3 patients had recently received a prescription for 4-AP 10 mg (one tablet) twice or three times daily, but testing of the tablets revealed that each 10 mg tablet contained between 90.1 mg to 125.6 mg of 4-AP. Following supportive care, all patients recovered from their acute illness, but were discharged with greater and chronic neurologic disability (Burton et al, 2008).
    2) The ingestion of approximately 0.6 mg/kg 4-aminopyridine produced symptoms which required hospital care in 2 adult men (Spyker et al, 1980).
    3) In the clinical setting, 1 mg/kg administered intravenously in postoperative patients has resulted in restlessness, confusion, and central nervous system excitation during the recovery period (Miller et al, 1976).
    4) Seizures were associated with a total daily dose of 100 mg in one adult, and did not recur after dosage reduction to 40 mg/day (McEvoy et al, 1989).
    5) CASE REPORT: A 45-year-old woman experienced tremors and dystonic choreoathetoid movements after ingesting a total of 35 mg of 4-aminopyridine, taken in 3 divided doses within a 10-hour period. The patient recovered with supportive care (De Cauwer et al, 2009).
    6) CASE REPORTS: Altered mental status was reported in two patients, with multiple sclerosis, who ingested 60 mg and 40 mg of dalfampridine, respectively, during clinical trials. The patient who had ingested 40 mg was exposed on two separate occasions, and also experienced a complex partial seizure after the first episode. Both patients recovered completely within 24 hours of exposure (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    7) CASE REPORT: A condition resembling limbic encephalitis and consisting of weakness, decreased awareness, memory loss, and hypophonic speech occurred in a patient with multiple sclerosis following an overdose ingestion of 300 mg dalfampridine. Although the patient's speech, language, and movement improved gradually, deficits in memory loss and the ability to learn new tasks persisted (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    B) AMIFAMPRIDINE
    1) CASE REPORT: A 65-year-old woman developed nausea, vomiting, paresthesias, generalized seizures, supraventricular tachycardia, and cardiac arrest after taking amifampridine (3,4-diaminopyridine) 60 mg 6 times daily for approximately 8 days instead of the prescribed 10 mg 6 times daily. With intensive supportive care, including successful resuscitation after the cardiac arrest, and discontinuation of the amifampridine, the patient made a complete recovery (Boerma et al, 1995).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 10 mg/kg (RTECS , 1991)
    B) LD50- (INTRAPERITONEAL)RAT:
    1) 6500 mcg/kg (RTECS , 1991)
    C) LD50- (ORAL)RAT:
    1) 21 mg/kg (RTECS , 1991)
    D) LD50- (SUBCUTANEOUS)RAT:
    1) 19 mg/kg (RTECS , 1991)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Dalfampridine is a broad spectrum potassium channel blocker; however, it is unknown how it exerts its therapeutic effect. Animal studies demonstrated an increase in conduction of action potentials in demyelinated axons through inhibition of potassium channels. Dalfampridine neither prolongs the QTc interval nor has any meaningful effect on the QRS duration (Prod Info AMPYRA(R) extended release oral tablets, 2010).
    B) Fampridine is a potassium channel blocking agent under investigation for a variety of neurological and neuromuscular disorders due to its ability to increase acetylcholine release at the neuromuscular junction as well as in the central nervous system (Hollander et al, 1986; Soni & Kam, 1982; Murray & Newsom-Davis, 1981). Similar to other monoamino and diamino derivatives of pyridine, the activity of fampridine as a potentiator of transmitter release is dependent upon the pyridine ring and the presence of an amino group (Soni & Kam, 1982).
    C) At the neuromuscular junction, fampridine facilitates presynaptic enhancement of cholinergic activity (Hollander et al, 1986). This appears to be related to potassium channel blocking activity, which prolongs the action potential and facilitates movement of calcium into the cell; the increased influx of calcium is felt to be responsible for enhancing release of acetylcholine (Davidson et al, 1988; Soni & Kam, 1982). Dalfampridine also appears to increase norepinephrine turnover (Davidson et al, 1988; Soni & Kam, 1982). The drug has no effect on sodium channels, and does not produce direct effects on the postsynaptic membrane (Soni & Kam, 1982). Fampridine crosses the blood-brain barrier and exhibits central cholinomimetic activity; norepinephrine turnover is enhanced whereas dopamine and serotonin turnover are essentially unaltered (van Diemen et al, 1993; Davidson et al, 1988; Carlsson et al, 1983; Soni & Kam, 1982). There is some evidence that fampridine may stimulate neurotransmitter synthesis (Hollander et al, 1986), although this remains to be confirmed.

Physicochemical

Molecular Weight

    A) 94.12

Animal Toxicology

Clinical Effects

    11.1.2) BOVINE/CATTLE
    A) Cattle drinking water containing 4-AP developed toxicity in 50% including diarrhea, incoordination, anorexia, weight loss, and behavioral changes (Nicholson & Prejean, 1981).
    11.1.5) EQUINE/HORSE
    A) Fever, bucking movements, sweating, seizures, and rapid eyelid fluttering were seen in horses that ate 1 kg of corn treated with 4-AP (Ray et al, 1978).

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Boerma CE, Rommes JH, van Leeuwen RB, et al: Cardiac arrest following an iatrogenic 3,4-diaminopyridine intoxication in a patient with Lambert-Eaton myasthenic syndrome. J Toxicol Clin Toxicol 1995; 33(3):249-251.
    3) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    4) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    5) Burton JM, Bell CM, Walker SE, et al: 4-aminopyridine toxicity with unintentional overdose in four patients with multiple sclerosis. Neurology 2008; 71(22):1833-1834.
    6) Carlsson C, Rosen I, & Nilsson E: Can 4-aminopyridine be used to reverse anaesthesia and muscle relaxation?. Acta Anaesthesiol Scand 1983; 27:87-90.
    7) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    8) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    9) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    10) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    11) Davidson M, Zemishlany Z, Mohs RC, et al: 4-Aminopyridine in the treatment of Alzheimer's disease. Biol Psychiatry 1988; 23:485-490.
    12) Davidson M, Zemishlany Z, Mohs RC, et al: 4-Aminopyridine in the treatment of Alzheimer's disease. Biol Psychiatry 1988a; 23:485-490.
    13) De Cauwer H, De Wolf P, Couvreur F, et al: An unusual case of 4-aminopyridine toxicity in a multiple sclerosis patient: epileptic disorder or toxic encephalopathy?. Acta Neurol Belg 2009; 109(1):40-41.
    14) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    15) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    16) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    17) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    18) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    19) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    20) Hollander E, Mohs RX, & Davis KL: Cholinergic approaches to the treatment of Alzheimer's disease. Br Med Bull 1986; 42:97-100.
    21) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    22) Johnson NC & Morgan MW: An unusual case of 4-aminopyridine toxicity. J Emerg Med 2006; 30(2):175-177.
    23) King AM, Menke NB, Katz KD, et al: 4-aminopyridine toxicity: a case report and review of the literature. J Med Toxicol 2012; 8(3):314-321.
    24) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    25) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    26) McEvoy KM, Windebank AJ, & Daube JR: 3,4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med 1989; 321:1567-1571.
    27) Miller RD, Booij LH, & Agoston S: 4-aminopyridine potentiates neostigmine and pyridostigmine in man. Anesthesiol 1976; 50:416-420.
    28) Murray NMF & Newsom-Davis J: Treatment with oral 4-aminopyridine in disorders of neuromuscular transmission. Neurology 1981; 31:265-271.
    29) Murray NMF & Newsom-Davis J: Treatment with oral 4-aminopyridine in disorders of neuromuscular transmission. Neurology 1981a; 31:265-271.
    30) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    31) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    32) Nicholson SS & Prejean CJ: Suspected 4-aminopyridine toxicosis in cattle. J Am Vet Med Assoc 1981; 178:1277.
    33) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    34) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    35) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    36) Product Information: AMPYRA(R) extended release oral tablets, dalfampridine extended release oral tablets. Acorda Therapeutics, Inc, Hawthorne, NY, 2010.
    37) Product Information: AMPYRA(R) oral extended release tablets, dalfampridine oral extended release tablets. Acorda Therapeutics (per FDA), Ardsley, NY, 2013.
    38) Product Information: FIRDAPSE oral tablets, amifampridine phosphate oral tablets. BioMarin Europe Limited (per EMA), London, United Kingdom, 2012.
    39) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    40) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    41) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 1991; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    42) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    43) Ray AC, Dwyer JN, & Fambro GW: Clinical signs and chemical confirmation of 4-aminopyridine poisoning in horses. Am J Vet Res 1978; 39:329-331.
    44) Schwid SR, Petrie MD, McDermott MP, et al: Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis. Neurology 1997; 48:817-821.
    45) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    46) Soni N & Kam P: 4-Aminopyridine - a review. Anaesth Intens Care 1982; 10:120-126.
    47) Soni N & Kam P: 4-Aminopyridine - a review. Anaesth Intens Care 1982a; 10:120-126.
    48) Spyker DA, Lynch C, & Shabanowitz J: Poisoning with 4-ap: report of three cases. Clin Tox 1980; 16:487-497.
    49) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    50) Stefoski D, Davis FA, & Faut M: 4-Aminopyridine improves clinical signs in multiple sclerosis. Ann Neurol 1987; 21:71-77.
    51) Stefoski D, Davis FA, Fitzsimmons WE, et al: 4-Aminopyridine in multiple sclerosis: prolonged administration. Neurology 1991; 41:1344-1348.
    52) Stefoski D, Davis FA, Fitzsimmons WE, et al: 4-Aminopyridine in multiple sclerosis: prolonged administration. Neurology 1991a; 41:1344-1348.
    53) Uges DRA, Sohn YJ, & Greijdanus B: 4-Aminopyridine kinetics. Clin Pharmacol Ther 1982; 31:587-593.
    54) Uges DRA, Sohn YJ, Greijdanus B, et al: 4-Aminopyridine kinetics. Clin Pharmacol Ther 1982a; 31:587-593.
    55) Wirtavuori K, Salmenpera M, & Tammisto T: Antagonism of d-tubocurarine-induced neuromuscular blockade with a mixture of 4-aminopyridine and neostigmine in man. Can Anaesth Soc J 1984; 31:624-630.
    56) van Diemen HAM, Polman CH, Koetsier JC, et al: 4-Aminopyridine in patients with multiple sclerosis: dosage and serum levels related to efficacy and safety. Clin Neuropharmacol 1993; 16:195-204.
    57) van Diemen HAM, Polman CH, Koetsier JC, et al: 4-Aminopyridine in patients with multiple sclerosis: dosage and serum levels related to efficacy and safety. Clin Neuropharmacol 1993a; 16:195-204.
    58) van Diemen HAM, Polman CH, van Dongen TMMM, et al: The effect of 4-aminopyridine on clinical signs in multiple sclerosis: a randomized, placebo-controlled, double-blind, cross-over study. Ann Neurol 1992; 32:123-130.