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FENFLURAMINE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Fenfluramine is an anorectic agent that has serotonin and some catecholamine- stimulating activity.
    B) Dexfenfluramine is the dextrorotatory stereoisomer of fenfluramine and is also used as an anorectic agent. It differs from fenfluramine in that it does not possess any catecholamine agonist activity.

Specific Substances

    A) FENFLURAMINE
    1) N-ethyl-A-methyl-3-trifluoro-methylphenethylamine
    2) S 768
    3) CAS 458-24-2 (Fenfluramine)
    4) CAS 404-82-0 (Fenfluramine hydrochloride)
    RELATED COMPOUNDS - DEXFENFLURAMINE
    1) Dextrofenfluramine
    2) (S)-N-ethyl-alpha-methyl-3-trifluoromethylphenethyl
    3) ----amine hydrochloride
    4) S-5614
    5) CAS 3239-44-9 (Dexfenfluramine)
    6) CAS 3239-45-0 (Dexfenfluramine hydrochloride)

Available Forms Sources

    A) FORMS
    1) FENFLURAMINE: 20 mg tablets (US); 20 mg tablets and 60 mg sustained-release capsules (GERMANY).
    2) DEXFENFLURAMINE: 15 mg capsules
    3) WITHDRAWAL FROM MARKET: As of September 1997, the USFDA had asked for the voluntary withdrawal of fenfluramine and dexfenfluramine based on reports of valvular heart disease associated with "fen-phen" (Department of Health & Human Services, 1997; (FDA MedWatch, 1997). The manufacturers (United States) have agreed with this recommendation.
    4) CHINESE HERB PRODUCT ADULTERATED WITH FENFLURAMINE - A woman developed fenfluramine poisoning after ingesting a Chinese herbal weight loss product adulterated with fenfluramine (Bryant et al, 2005).
    B) USES
    1) FENFLURAMINE has primarily been used as a short-term weight reducing agent; however, some studies have demonstrated limited efficacy in the treatment of autism.

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) OVERDOSE
    1) ONSET - The onset of signs and symptoms following fenfluramine overdose is rapid with a relatively short interval between ingestion and death, and a lack of response to normal resuscitative measures.
    2) EFFECTS - Tachycardia, hypertension, diaphoresis, mydriasis seizures and nystagmus man develop within 1/2 to 3 1/2 hours post-ingestion. In severe cases, respiratory failure, coma, dysrhythmias and cardiovascular collapse may occur within the first 4 hours post-ingestion.
    3) DURATION of toxicity (drowsiness, ataxia, tachycardia, and mydriasis) may be up to 2 to 3 days.
    4) DOSE - As little as 4.6 mg/kg has been associated with coma and seizures. Doses exceeding 28.7 mg/kg have been associated with fatalities. Terminal events appear either to be neurologic or cardiac in nature and are accompanied by rapid onset and progression of symptoms.
    B) ADVERSE EFFECTS
    1) Based on new evidence of increased risk of valvular heart disease associated with fenfluramine and dexfenfluramine use, the FDA (September 1997) has called for the voluntary withdrawal of these drugs.
    0.2.4) HEENT
    A) Mydriasis and nystagmus may commonly occur following a fenfluramine overdose.
    B) Diplopia has been reported in association with the use of dexfenfluramine.
    0.2.5) CARDIOVASCULAR
    A) Various cardiac dysrhythmias, including tachycardia and ventricular fibrillation may occur with fenfluramine and dexfenfluramine use.
    B) Cardiac depression leading to cardiac arrest can occur within 4 hours post-ingestion of fenfluramine.
    C) Myocardial infarction and mild hypotension have been reported following dexfenfluramine use.
    D) Valvular heart disease has been associated with fenfluramine and dexfenfluramine use.
    E) Mild hypertension was reported following a dexfenfluramine overdose.
    0.2.6) RESPIRATORY
    A) Severe and intractable pulmonary hypertension has been reported following fenfluramine and dexfenfluramine use.
    B) Respiratory failure has occurred with a fenfluramine and dexfenfluramine overdoses.
    C) Recurrent interstitial pneumonitis has been reported with dexfenfluramine use.
    0.2.7) NEUROLOGIC
    A) Cerebral hemorrhage, somnolence, dizziness, agitation and coma have been reported following fenfluramine and dexfenfluramine use.
    B) Seizures and coma may occur with fenfluramine and dexfenfluramine overdoses.
    0.2.8) GASTROINTESTINAL
    A) Vomiting, abdominal pain, and incontinence may occur with fenfluramine poisonings.
    0.2.18) PSYCHIATRIC
    A) Depression, psychosis, and mania have been reported following fenfluramine and dexfenfluramine use. Hallucinations may occur.
    0.2.20) REPRODUCTIVE
    A) Fenfluramine is in pregnancy category C.
    0.2.22) OTHER
    A) The combination of fenfluramine and phentermine has been reported to result in valvular heart disease.

Laboratory Monitoring

    A) Fenfluramine blood levels are not clinically useful.
    B) Obtain an ECG and institute continuous cardiac monitoring.
    C) Echocardiogram may be indicated if valvular insufficiency or a new murmur is present on exam. Because many patients have valvular disease in the absence of clinical evidence of valvular insufficiency or murmurs, consider performing an echocardiogram on any patient who has taken the drug longer than 3 months.
    D) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) WHOLE BOWEL IRRIGATION - Delayed-release fenfluramine ingestions may need whole bowel irrigation, as a decontamination method, using polyethylene glycol electrolyte solution via a nasogastric tube.
    C) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    D) Monitor EKG and vital signs regularly.
    E) HEMODIALYSIS should be considered in patients with renal failure.
    F) CARDIAC DYSRHYTHMIAS - Esmolol is useful for the management of severe tachycardia. Lidocaine should be used in the presence of ventricular extrasystoles.
    G) HYPERPYREXIA should be treated with external body cooling.

Range Of Toxicity

    A) Acute fenfluramine ingestion of more than 28.7 mg/kg has been associated with fatalities. Survival has been reported with 25 to 70 mg/kg. As little as 4.6 to 6.2 mg/kg of fenfluramine has caused seizures and coma. As little as 3 mg/kg has produced mydriasis and tachycardia.

Clinical Effects

Summary Of Exposure

    A) OVERDOSE
    1) ONSET - The onset of signs and symptoms following fenfluramine overdose is rapid with a relatively short interval between ingestion and death, and a lack of response to normal resuscitative measures.
    2) EFFECTS - Tachycardia, hypertension, diaphoresis, mydriasis seizures and nystagmus man develop within 1/2 to 3 1/2 hours post-ingestion. In severe cases, respiratory failure, coma, dysrhythmias and cardiovascular collapse may occur within the first 4 hours post-ingestion.
    3) DURATION of toxicity (drowsiness, ataxia, tachycardia, and mydriasis) may be up to 2 to 3 days.
    4) DOSE - As little as 4.6 mg/kg has been associated with coma and seizures. Doses exceeding 28.7 mg/kg have been associated with fatalities. Terminal events appear either to be neurologic or cardiac in nature and are accompanied by rapid onset and progression of symptoms.
    B) ADVERSE EFFECTS
    1) Based on new evidence of increased risk of valvular heart disease associated with fenfluramine and dexfenfluramine use, the FDA (September 1997) has called for the voluntary withdrawal of these drugs.

Vital Signs

    3.3.3) TEMPERATURE
    A) FEVER, accompanied by flushed face, sweating, and shivering, may occur with fenfluramine overdose (Koury et al, 1999; Fleisher & Campbell, 1969; Riley et al, 1969; Von Muhlendahl & Krienke, 1979).
    1) CASE REPORT - Koury et al (1999) reported a case of combined fenfluramine and phentermine overdose (diphenhydramine and meperidine were also involved) with sympathetic storm (tachycardia, mydriasis, fever, diaphoresis, hyperventilation, and combativeness). The patient developed respiratory distress syndrome requiring continued intubation and mechanical ventilation for 12 days.
    3.3.4) BLOOD PRESSURE
    A) HYPOTENSION - Mild hypotension has been reported following therapeutic doses of dexfenfluramine (Andersson et al, 1991).

Heent

    3.4.1) SUMMARY
    A) Mydriasis and nystagmus may commonly occur following a fenfluramine overdose.
    B) Diplopia has been reported in association with the use of dexfenfluramine.
    3.4.3) EYES
    A) MYDRIASIS - Dilated and non-reactive pupils may be noted with fenfluramine overdose (Richards, 1969) White et al, 1967).
    1) CASE REPORT - Koury et al (1999) reported a case of combined fenfluramine and phentermine overdose (diphenhydramine and meperidine were also involved) with sympathetic storm (tachycardia, mydriasis, fever, diaphoresis, hyperventilation, and combativeness).
    B) NYSTAGMUS - Rotary nystagmus has been reported with an overdose of fenfluramine   (Riley et al, 1969).
    1) CASE REPORT - After ingesting 120 10-mg tablets of a Chinese herbal weigh loss product adulterated with fenfluramine, a woman presented to the ED comatose, tachycardic (120 beats/min), and hypotensive (BP 80/60 mm Hg). Eye examination revealed 8-mm pupils bilaterally, with horizontal nystagmus. Following supportive care, she recovered without further sequelae (Bryant et al, 2005).
    C) BLURRED VISION - Blurring may be noted following a fenfluramine overdose (Riley et al, 1969).
    D) DIPLOPIA - Progressive diplopia secondary to internuclear ophthalmoplegia occurred 48 to 72 hours after initiating therapy with dexfenfluramine, 25 mg every 8 hours, and tiratricol, 0.75 mg every 8 hours. Symptoms disappeared 48 hours after discontinuation of the medications.
    1) Rechallenge with the medications, now given every 12 hours, caused a second onset of the diplopia. The medications were discontinued and the diplopia completely resolved 27 days later (Carreres et al, 1992).
    3.4.6) THROAT
    A) HALITOSIS - Aman et al (1991) reported the development of a peculiar body odor and halitosis, in a child, that occurred at the same time as administration of fenfluramine.

Cardiovascular

    3.5.1) SUMMARY
    A) Various cardiac dysrhythmias, including tachycardia and ventricular fibrillation may occur with fenfluramine and dexfenfluramine use.
    B) Cardiac depression leading to cardiac arrest can occur within 4 hours post-ingestion of fenfluramine.
    C) Myocardial infarction and mild hypotension have been reported following dexfenfluramine use.
    D) Valvular heart disease has been associated with fenfluramine and dexfenfluramine use.
    E) Mild hypertension was reported following a dexfenfluramine overdose.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Fenfluramine poisoning effects may include tachycardia, extrasystoles, asystole, and ventricular fibrillation (Gold et al, 1969; Fleisher & Campbell, 1969; Veltri & Temple, 1975).
    b) CASE REPORT - A 23-year-old female ingested 1800 mg dexfenfluramine and subsequently developed tachycardia with a heart rate of 162 beats per minute (LoVecchio & Curry, 1998).
    c) A retrospective chart review was conducted of all fenfluramine and dexfenfluramine ingestions reported to six regional poison centers from 1993 to 1996 with 132 cases identified (58 adults and 74 children). Twelve of the 58 adults developed tachycardia. The lowest dose associated with tachycardia was 300 mg fenfluramine and 150 mg dexfenfluramine (Spiller et al, 1997).
    1) Two of the 74 children also experienced tachycardia with the lowest dose/ weight ratio being 11.6 mg/kg.
    d) CASE REPORT - Koury et al (1999) reported a case of combined fenfluramine and phentermine overdose with sympathetic storm (tachycardia, mydriasis, fever, diaphoresis, hyperventilation, and combativeness). He developed respiratory distress syndrome requiring continued intubation and mechanical ventilation for 12 days.
    e) CASE REPORT - After ingesting 120 10-mg tablets of a Chinese herbal weigh loss product adulterated with fenfluramine, a woman presented to the ED comatose, tachycardic (120 beats/min) and hypotensive (BP 80/60 mm Hg). Following supportive care, she recovered without further sequelae (Bryant et al, 2005).
    B) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) Cardiac depression leading to cardiac arrest can occur within 4 hours post-ingestion of fenfluramine (Gold et al, 1969).
    C) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) Myocardial infarction was associated with the use of 45 mg/day of dextrofenfluramine for 8 days. The woman had lost 10% of body weight and there may have been fluid-electrolyte abnormalities (Evrard & Allaz, 1990; Bain & Rowe, 1990).
    D) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) A mild decrease in both systolic and diastolic pressure was seen in patients treated with 30 mg/day of dexfenfluramine for 4 days (Andersson et al, 1991).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - After ingesting 120 10-mg tablets of a Chinese herbal weigh loss product adulterated with fenfluramine, a woman presented to the ED comatose, tachycardic (120 beats/min) and hypotensive (BP 80/60 mm Hg). Following supportive care, she recovered without further sequelae (Bryant et al, 2005).
    E) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Mild hypertension (160/88 mmHg) was reported in a 23-year-old female following an ingestion of 1800 mg dexfenfluramine (LoVecchio & Curry, 1998).
    b) A retrospective chart review was conducted of all fenfluramine and dexfenfluramine ingestions reported to six regional poison centers from 1993 to 1996, with 132 cases identified (58 adults and 74 children). Nine adults developed hypertension with the lowest dose associated with hypertension being 300 mg fenfluramine and 150 mg dexfenfluramine (Spiller et al, 1997).
    F) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) VALVULAR HEART DISEASE has been associated with fenfluramine in combination with phentermine, fenfluramine alone, dexfenfluramine alone, or dexfenfluramine in combination with phentermine (Teramae et al, 2000; Biswas et al, 1999; Hensrud et al, 1999; Weissman et al, 1998; Wee et al, 1998; FDA MedWatch, 1997). Phentermine alone has not been associated with valvular disease (FDA MedWatch, 1997).
    1) In most studies, the use of these appetite-suppressants for 4 months or longer has been associated with an increased risk of valvular disease (Ryan et al, 1999; Kancherla et al, 1999; Jick et al, 1998). In one study, cardiac valve abnormalities were observed in 22.7% of patients receiving an appetite suppressant compared to 1.3% of control subjects (Khan et al, 1998).
    2) It presents often as multivalvular, primarily affecting the mitral and aortic valves (Connolly et al, 1997; Graham & Green, 1997; Nightingale, 1997). Echocardiographic studies indicated unusual valvular morphology (Connolly et al, 1997 & Cannistra et al, 1997). The results of a study involving 1466 patients indicate that use of dexfenfluramine or phentermine/fenfluramine is associated with an increase in the prevalence of aortic regurgitation, but not mitral regurgitation according to FDA echocardiographic criteria. The prevalence of serious cardiac events (eg; myocardial infarction, heart failure, ventricular dysrhythmias, endocarditis) at any point was not significantly different in treated and untreated groups (Gardin et al, 2000). A follow-up study, involving 1142 of the 1466 patients who participated in the original study, was conducted to clinically and echocardiographically evaluate any valvular changes that may have occurred approximately 1 year after the initial echocardiogram and approximately 18 months after discontinuation of dexfenfluramine or phentermine/fenfluramine. Primary endpoints of the study were a change in aortic or mitral regurgitation grade and any new cardiovascular symptoms and physical findings. Results of the study showed that the aortic valve recordings and mitral valve images were comparable in 97.6% (n=1114) and 96.8% (n=1106) of the participants (both treated patients as well as controls), respectively. There were no significant differences between the treated patients and the controls in reporting new cardiovascular symptoms or physical findings (Gardin et al, 2001).
    3) These findings and 66 further cases reported to the FDA, prompted the voluntary withdrawal of fenfluramine and dexfenfluramine in September 1997 from the US market (FDA MedWatch, 1997).
    4) In a study of human and porcine heart valves, the fenfluramine metabolite, norfenfluramine, was found to have a high affinity for 5-HT2B receptors, similar to that of ergot drugs or 5-HT released from carcinoid tumors, conditions known to result in valvular damage. This may contribute to valvular fibroplasia in humans (Fitzgerald et al, 2000).
    b) Several studies have reported that the incidence of valvular disease does not correlate with the duration of therapy (Teramae et al, 2000; Li et al, 1999; Burger et al, 1999).
    1) In one study, the severity of cardiac valvulopathy was associated with fenfluramine dosage, but not with phentermine dosage or duration of use. The proportion of patients with severe valvulopathy increased from 20% to 66%, as the fenfluramine dosage increased from less than or equal to 40 milligrams/day to greater than or equal to 60 milligrams/day (Li et al, 1999).
    2) In another study, prevalence of valvular regurgitation was found to be similar to the normal offspring in the Framington Heart Study, who were similar in age, gender and geographical location (Burger et al, 1999). Kancherla et al (1999) reported that severe valvular regurgitation is a rare complication of anorexigen exposure.
    3) It has been suggested that valve abnormalities among users of fen-phen may not always be attributable to the combination, and therefore the incidence of valvular heart disease among fen-phen users may be less common than previously estimated. Other possible etiologies such as age-related degenerative changes, serotonin excess from exposure to other medications, or other patient specific conditions may have contributed to the development of valve abnormalities (Kimmel et al, 1999; Burger et al, 1999; Schiller, 1999; Wee et al, 1998).
    4) In one study, the progression of fenfluramine-associated valvular heart disease was evaluated by echocardiography. In most patients, valvular regurgitation improved or remained stable after therapy ended. However, a few patients experienced worsening of valvular function (Mast et al, 2001).
    5) In another study, echocardiographic comparison of baseline and 1-year studies revealed decreased severity of aortic regurgitation in patients who took dexfenfluramine for 2 to 3 months compared with those who took placebo (Weissman et al, 2001).
    c) CASE REPORT - Restrictive cardiomyopathy and endocardial fibrosis were reported in a 35-year-old woman after use of fenfluramine and phentermine for 5 months. The patient had mild mitral and tricuspid regurgitation with right atrial enlargement. A right ventricular biopsy revealed a thick myocardium with extensive fibrosis and collagen without inflammation (Fowles et al, 1998).
    d) CASE REPORT - Discontinuation of fenfluramine and phentermine in a 44-year-old woman who had developed moderate to severe valvular dysfunction resulted in regression of disease, with improved ventricular function and dramatic improvement of regurgitant lesions (Cannistra & Cannistra, 1998).
    e) CASE REPORT - A 44-year-old female developed severe mitral and tricuspid regurgitation and pulmonary hypertension after taking fen-phen for 2 years at doses of 60 to 240 milligrams/day fenfluramine and 90 to 180 milligrams/day phentermine. Her identical twin sister remains symptom free with normal echocardiographic findings after 2 years of treatment with fenfluramine 60 milligrams/day and phentermine 24 milligrams/day, suggesting a dose-related effect in the development of toxicity (Tovar et al, 1999).
    f) CASE REPORT - A cardiac allograft transplanted from a donor with prolonged exposure to fen-phen (60 mg/d fenfluramine, 30 mg/d phentermine over 8 months) demonstrated valvular lesions prior to transplant, but only trivial mitral regurgitation. At 6 months follow-up, echocardiography demonstrated worsening mitral regurgitation to moderate severity, suggesting the valvulopathy may progress despite removal from the causative environment (Prasad et al, 1999).

Respiratory

    3.6.1) SUMMARY
    A) Severe and intractable pulmonary hypertension has been reported following fenfluramine and dexfenfluramine use.
    B) Respiratory failure has occurred with a fenfluramine and dexfenfluramine overdoses.
    C) Recurrent interstitial pneumonitis has been reported with dexfenfluramine use.
    3.6.2) CLINICAL EFFECTS
    A) PULMONARY HYPERTENSION
    1) WITH THERAPEUTIC USE
    a) Primary pulmonary hypertension has been reported with fenfluramine use (Teramae et al, 2000; Tovar et al, 1999; Hensrud et al, 1999; Douglas et al, 1981; Pouwels et al, 1990; Brenot et al, 1993) including two cases of severe and intractable pulmonary hypertension (McMurray et al, 1986; Fotiadis et al, 1991; McCann et al, 1997). In one study, pulmonary artery pressures decreased to near normal in the subject with pulmonary hypertension, suggesting that echocardiographic features appeared to improve over the short term after cessation of the drugs (Hensrud et el, 1999).
    b) Three lethal cases of primary pulmonary hypertension were reported following dexfenfluramine use. Two patients had taken dexfenfluramine intermittently for 12 months, and one patient had taken dexfenfluramine continuously over a 6-month period (Atanassoff et al, 1992; Cacoub et al, 1995).
    c) Fatal pulmonary hypertension has been reported after short-term combination use of fenfluramine and phentermine. One patient, a 29-year-old female died 8 months after taking the combination for 23 days (Mark et al, 1997). Another 30-year-old woman developed progressive dyspnea and edema after using fenfluramine and phentermine for 4 weeks. The anorexiant drugs were discontinued, but the patient was subsequently diagnosed with pulmonary hypertension and died approximately 9 months later (Dillon et al, 1997).
    d) CASE REPORT - A 39-year-old woman developed rapidly progressing, fatal pulmonary hypertension following administration of phentermine-fenfluramine for 9 months. Autopsy revealed pulmonary vascular lesions affecting varying-sized arteries most consistent with thrombotic arteriopathy (Strother et al, 1999).
    e) Comparing the outcome of patients with fenfluramine-induced pulmonary hypertension (n=10) with patients diagnosed with primary pulmonary hypertension (n=70) showed that the patients with fenfluramine-induced pulmonary hypertension (PH) had a poorer survival rate than patients with primary pulmonary hypertension (PPH). The 1-year survival rate was 53% in the fenfluramine PH group as compared with 89% in the PPH group. The 5-year survival rate was 18% in the fenfluramine PH group as compared with 39% in the PPH group. There were no significant differences in the baseline demographics or hemodynamics of either group and epoprostenol therapy was intravenously administered to both groups for treatment of the pulmonary hypertension (Rich et al, 2003). Because of the poor survival rate in the fenfluramine PH group, despite epoprostenol treatment on presentation, the authors suggest that fenfluramine may induce a pathogenic mechanism that is resistent to intravenous epoprostenol or other established therapies for pulmonary hypertension.
    B) ACUTE RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) Hypoventilation and respiratory failure has occurred with fenfluramine and dexfenfluramine overdoses (Fleisher & Campbell, 1969; Riley et al, 1969; LoVecchio & Curry, 1998).
    C) INTERSTITIAL PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 39-year-old male experienced three separate episodes of dyspnea and non-productive coughing that occurred while taking dexfenfluramine, 15 mg twice daily. Chest radiographs revealed bilateral interstitial infiltrates and pleural effusion that is indicative of interstitial pneumonitis (Braun et al, 1993).
    D) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Koury et al (1999) reported a case of combined fenfluramine and phentermine overdose (diphenhydramine and meperidine were also involved) with sympathetic storm (tachycardia, mydriasis, fever, diaphoresis, hyperventilation, and combativeness). He developed respiratory distress syndrome requiring continued intubation and mechanical ventilation for 12 days.

Neurologic

    3.7.1) SUMMARY
    A) Cerebral hemorrhage, somnolence, dizziness, agitation and coma have been reported following fenfluramine and dexfenfluramine use.
    B) Seizures and coma may occur with fenfluramine and dexfenfluramine overdoses.
    3.7.2) CLINICAL EFFECTS
    A) CEREBRAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) A 56-year-old female developed a cerebral hemorrhage while taking a combination of fenfluramine and phentermine at the prescribed dose. Resolution of the hematoma occurred within 3 months with no residual sequelae (Wen et al, 1997). However, Derby et al (1999) do not support a substantial increased risk of stroke attributable to the use of fenfluramine, dexfenfluramine, or phentermine in young relatively healthy obese patients in a large cohort study.
    B) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) A retrospective chart review was conducted of all fenfluramine and dexfenfluramine ingestions reported to six regional poison centers from 1993 to 1996. Lightheadedness/dizziness was reported in 9 of 58 adults and 2 of 74 children (Spiller et al, 1997).
    C) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) A retrospective chart review was conducted of all fenfluramine and dexfenfluramine ingestions reported to six regional poison centers from 1993 to 1996. Agitation was reported in 4 of 58 adults and in 1 of 74 children. In children, the lowest dose/weight ration associated with agitation was 11.6 mg/kg (Spiller et al, 1997).
    D) DROWSY
    1) WITH POISONING/EXPOSURE
    a) A female patient slept for 72 hours after taking a single dose of dexfenfluramine (Byrne, 1992).
    b) A study involving the clinical effects of fenfluramine, conducted by Aman et al (1991), revealed that drowsiness occurred in some of the children involved in the study.
    c) A retrospective chart review was conducted of all fenfluramine and dexfenfluramine ingestions reported to six regional poison centers from 1993 to 1996. Lethargy was reported in 11 of 58 adults and 1 of 74 children (Spiller et al, 1997).
    E) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Jaw tremors and seizures have occurred following fenfluramine overdoses (Koury et al, 1999; Campbell & Moore, 1969; Fleisher & Campbell, 1969; Gold et al, 1969; Richards, 1969; Riley et al, 1969).
    b) Von Muhlendahl and Krienke (1979) reviewed 38 cases of fenfluramine poisoning. Ten patients developed seizures and became comatose, despite rapid and adequate treatment for fenfluramine poisoning.
    1) The seizures occurred 30 minutes to 3.5 hours after ingestion of fenfluramine.
    c) CASE REPORT - A 23-year-old female developed tonic-clonic seizures, involving the lower extremities, after ingesting 1800 mg dexfenfluramine. The seizures were refractory to the intravenous administration of diazepam, and only resolved following succinylcholine-induced paralysis (LoVecchio & Curry, 1998).
    d) A retrospective chart review was conducted of all fenfluramine and dexfenfluramine ingestions reported to six regional poison centers from 1993 to 1996. Two of the 58 adults identified developed seizures. The lowest dose associated with the development of seizures was 1200 mg of fenfluramine (Spiller et al, 1997).
    F) COMA
    1) WITH POISONING/EXPOSURE
    a) Ten of 38 patients developed seizures and became comatose following fenfluramine poisoning, despite rapid and adequate treatment for the poisoning (Von Muhlendahl & Krienke, 1979).
    1) Coma was noted in doses as low as 4.6 mg/kg.
    b) CASE REPORT - A 23-year-old female ingested 1800 mg dexfenfluramine and, 2 hours later, presented with coma, responsive only to noxious stimuli. The patient woke 30 hours after presentation and made a complete recovery 48 hours after presentation (LoVecchio & Curry, 1998).
    c) A retrospective chart review was conducted of all the fenfluramine and dexfenfluramine ingestions reported to six regional poison centers from 1993 to 1996. One of the 58 adults identified became comatose. The lowest dose associated with coma was 1200 mg of fenfluramine (Spiller et al, 1997).
    d) CASE REPORT - After ingesting 120 10-mg tablets of a Chinese herbal weigh loss product adulterated with fenfluramine, a woman presented to the ED comatose, tachycardic (120 beats/min) and hypotensive (BP 80/60 mm Hg). Following supportive care, she recovered without further sequelae (Bryant et al, 2005).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEUROPATHY
    a) ANIMAL STUDIES - Brain serotonin neurotoxicity (long-lasting reductions in serotonin axonal markers) has been reported in all the animal species tested and with all routes of drug administration; to date, human implications are not known (McCann et al, 1997).

Gastrointestinal

    3.8.1) SUMMARY
    A) Vomiting, abdominal pain, and incontinence may occur with fenfluramine poisonings.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Vomiting and incontinence of feces may be noted with fenfluramine poisoning (Richards, 1969; Veltri & Temple, 1975).
    B) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain or burning in the epigastrium may be noted following an overdose of fenfluramine (Gold et al, 1969; Riley et al, 1969).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ANION GAP
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - After ingesting 120 10-mg tablets of a Chinese herbal weigh loss product adulterated with fenfluramine, a woman presented to the ED comatose, tachycardic (120 beats/min) and hypotensive (BP 80/60 mm Hg). Laboratory results revealed an anion gap of 18. Following supportive care, she recovered without further sequelae (Bryant et al, 2005).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN NECROSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 44-year-old male with non-insulin dependent diabetes mellitus developed pain and discoloration of the left index and small fingers two months after beginning dexfenfluramine therapy, 15 mg twice daily, to treat mild obesity. Both digital arteries of the index and small fingers were occluded. Dexfenfluramine was discontinued, but the lesions progressed to necrosis despite treatment with nitrates, Bupivacaine and nifedipine, ultimately requiring amputation of the fingers (Marinella & Berrettoni, 1997).
    1) Upon rechallenge of the dexfenfluramine, the patient experienced mild discoloration of several fingers of the right hand. The discoloration did not progress upon discontinuation of the dexfenfluramine.
    B) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Koury et al (1999) reported a case of combined fenfluramine and phentermine overdose (diphenhydramine and meperidine were also involved) with sympathetic storm (tachycardia, mydriasis, fever, diaphoresis, hyperventilation, and combativeness). Th patient developed respiratory distress syndrome requiring continued intubation and mechanical ventilation for 12 days.

Reproductive

    3.20.1) SUMMARY
    A) Fenfluramine is in pregnancy category C.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    FENFLURAMINEC
    Reference: Briggs et al, 1998

Genotoxicity

    A) In a human cell line culture, d-fenfluramine was found to be cytotoxic to the serotonin transporter expressing human placental choriocarcinoma cells, causing DNA fragmentation and apoptosis, a possible mechanism associated with human toxicity (Bengel et al, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Fenfluramine blood levels are not clinically useful.
    B) Obtain an ECG and institute continuous cardiac monitoring.
    C) Echocardiogram may be indicated if valvular insufficiency or a new murmur is present on exam. Because many patients have valvular disease in the absence of clinical evidence of valvular insufficiency or murmurs, consider performing an echocardiogram on any patient who has taken the drug longer than 3 months.
    D) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise indicated.

Methods

    A) OTHER
    1) Fenfluramine is detectable in blood and urine within 1 to 2 hours after ingestion (Koury et al, 1999).
    2) Urine drug screen may reveal sympathetic amines (Koury et al, 1999).
    B) CHROMATOGRAPHY
    1) Gas chromatography/mass spectroscopy has been used to measure serum levels of fenfluramine and norfenfluramine (Bryant et al, 2005).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Fenfluramine blood levels are not clinically useful.
    B) Obtain an ECG and institute continuous cardiac monitoring.
    C) Echocardiogram may be indicated if valvular insufficiency or a new murmur is present on exam. Because many patients have valvular disease in the absence of clinical evidence of valvular insufficiency or murmurs, consider performing an echocardiogram on any patient who has taken the drug longer than 3 months.
    D) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) 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).
    B) WHOLE BOWEL IRRIGATION (WBI)
    1) Whole bowel irrigation may be an alternative method of decontamination following delayed-release fenfluramine ingestions.
    2) Concomitant therapy included balanced electrolyte solution and H2- antagonists.
    a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.
    1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.
    b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
    c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
    d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.
    6.5.3) TREATMENT
    A) SEIZURE
    1) DIAZEPAM
    a) The cases of two children treated with diazepam are noteworthy. One child, a 3 1/2-year-old female, ingested 1,120 milligrams (70 milligrams/kilogram) and attained a plasma level at 7.5 hours of 1.14 micrograms/milliliter (Darmandy, 1974).
    b) The second, a 2-year 11-month-old male, ingested 440 milligrams (30 milligrams/kilogram) and attained a plasma level at 5.25 hours of 0.47 microgram/milliliter (Darmandy, 1974).
    c) The treatment of these children was unique in that they both received higher than recommended doses of diazepam, administered in slow intravenous boluses of 5 milligrams repeated as needed to control recurrent muscle spasms.
    1) Total doses were 45 milligrams and 30 milligrams, respectively. Both children tolerated the high doses well with no evidence of respiratory depression or hypotension, and recovered completely.
    d) Although their treatment included other procedures, such as induced emesis and gastric lavage (which have been done in other cases, both fatal and nonfatal), the reporting author attributed his success to the high doses of diazepam and suggested the drug to have effects antagonistic to those of fenfluramine HCl.
    2) 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).
    3) 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 .
    4) 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).
    5) 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, 2010; Chin et al, 2008).
    6) 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).
    7) 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).
    B) MONITORING OF PATIENT
    1) Monitor cardiac function.
    2) Due to the following reasons, it has been recommended that an echocardiogram be performed on any patient who has taken the drug longer than 3 months: audible murmurs are present in a minority of patients with valvular dysfunction; patients may not be symptomatic until late in the course of valvular disease; the incidence of valvular disease appears to increase with increasing duration of therapy (Pi-Sunyer, 1999).
    C) TACHYARRHYTHMIA
    1) TACHYCARDIA SUMMARY
    a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
    b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    c) ESMOLOL/ADULT LOADING DOSE
    1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).
    d) ESMOLOL/ADULT MAINTENANCE DOSE
    1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
    2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
    3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    e) CAUTION
    1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).
    D) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    E) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) May be treated by external body cooling.
    F) SEROTONIN SYNDROME
    1) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    2) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    3) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    4) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    5) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    6) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2010; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    7) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    8) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Dialysis may be of value if renal function is inadequate.

Range Of Toxicity

Summary

    A) Acute fenfluramine ingestion of more than 28.7 mg/kg has been associated with fatalities. Survival has been reported with 25 to 70 mg/kg. As little as 4.6 to 6.2 mg/kg of fenfluramine has caused seizures and coma. As little as 3 mg/kg has produced mydriasis and tachycardia.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) FENFLURAMINE -
    a) Wyeth-Ayerst Laboratories (American Home Products Corporation) voluntarily withdrew fenfluramine (Pondimin(R)) from the United States market on September 15, 1997 following reports of heart valve abnormalities in patients using this medication. The data in this management are included for completeness only.
    b) ORAL - Usual initial dose is 20 milligrams three times daily 1 hour before meals increasing as needed to a recommended maximum oral dose of 40 milligrams three times daily 1 hour before meals (Prod Info Pondimin(R), fenfluramine, 1997).
    1) Depending on the degree of effectiveness and side effects, the dosage may be increased at weekly intervals by one tablet daily until maximum of 2 tablets three times daily is attained (Prod Info Pondimin(R), fenfluramine, 1997).
    2) In patients in whom the initial dosage is not well tolerated, dosage may be reduced to 2 tablets daily and thereafter gradually increased in order to minimize the chance of side effects (Prod Info Pondimin(R), fenfluramine, 1997).
    2) DEXFENFLURAMINE -
    a) ORAL - 15 milligrams twice daily, preferably at mealtimes (Reynolds, 1993).
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) INFANTILE AUTISM -
    a) Fenfluramine administration (1.5 milligrams/kilogram/day) was reported effective in decreasing blood serotonin concentrations and reducing behavioral symptoms (motor activity, distractibility, and mood disturbances) in infants with autism after 4 months of treatment (August et al, 1984).
    b) Recently its efficacy for autism has been questioned (Ho, 1986; August et al, 1987).

Minimum Lethal Exposure

    A) SPECIFIC SUBSTANCE
    1) FENFLURAMINE
    a) The range of reported fatal dose is from 2,000 milligrams (Fleisher & Campbell, 1969) to less than 4,000 milligrams (200 tablets shared among 3 children) (Gold et al, 1969).
    b) In a review of 53 fenfluramine intoxications, 10 deaths occurred with doses of 28.7 to 70 milligrams/kilogram. Nine patients died following cardiac arrest, which occurred from 1 to 4 hours post-ingestion.
    1) Other symptoms included nystagmus, hypertonia, trismus, hyperreflexia, clonus, excitation, hyperthermia, and sweating occurring from 30 to 60 minutes post-ingestion and persisting several days (Von Muhlendahl & Krienke, 1979).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) FENFLURAMINE
    a) Coma and seizures have occurred in doses as low as 4.6 milligrams/kilogram (Von Muhlendahl & Krienke, 1979).
    b) Mydriasis and tachycardia have occurred following doses of 3 milligrams/ kilogram (Von Muhlendahl & Krienke, 1979).
    c) The reported nonfatal range is from 1,600 milligrams (Richards, 1969) to less than 4,000 milligrams shared among 3 children (Gold et al, 1969).
    d) The highest reported milligram/kilogram dose (70 milligrams/kilogram) was fatal in one patient (Simpson et al, 1975) and nonfatal in another (Darmandy, 1974).
    e) Survival has been reported with doses between 25 and 70 milligrams/kilogram (Darmandy, 1974).
    f) A retrospective chart review was conducted of all fenfluramine ingestions reported to six regional poison centers from 1993 to 1996. The lowest dose of fenfluramine associated with seizures or coma in adults was 1.2 grams. The lowest fenfluramine dose associated with hypertension or tachycardia, in adults, was 300 milligrams (Spiller et al, 1997).
    2) DEXFENFLURAMINE
    a) A female patient slept solidly for 72 hours after ingesting 15 milligrams of dexfenfluramine (Byrne, 1992).
    b) Ingestion of 1800 milligrams of dexfenfluramine resulted in respiratory failure, tonic-clonic seizures, and coma (LoVecchio & Curry, 1998).
    c) A retrospective chart review was conducted of all dexfenfluramine ingestions reported to six regional poison centers from 1993 to 1996. The lowest dexfenfluramine dose associated with hypertension or tachycardia was 150 milligrams (Spiller et al, 1997).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) FENFLURAMINE
    1) Therapeutic plasma concentrations are in the range of 0.05 to 0.15 micrograms/milliliter (Kintz & Mangin, 1992).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) FENFLURAMINE
    1) In one report, the highest reported non-fatal blood level was 110 micrograms/deciliter at 7.5 hours post-ingestion (Darmandy, 1974). In another report, the highest reported non-fatal blood level was 280 micrograms/deciliter (Koury et al, 1999).
    2) Fatal blood levels range from 650 micrograms/deciliter to 2800 micrograms/deciliter (Fleisher & Campbell, 1969; Gold et al, 1969; Veltri & Temple, 1975).
    3) CHINESE HERBS - After ingesting 120 10-mg tablets of a Chinese herbal weigh loss product adulterated with fenfluramine, a woman presented to the ED comatose, tachycardic (120 beats/min), and hypotensive (BP 80/60 mm Hg). Serum concentrations of fenfluramine and norfenfluramine were 2,480 ng/mL (therapeutic 35 to 380 ng/mL) and 330 ng/mL (steady state levels after daily doses 60 to 160 ng/mL), respectively. Following supportive care, she recovered without further sequelae (Bryant et al, 2005).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Fenfluramine hydrochloride is a sympathomimetic agent which appears to have no stimulant effect upon the central nervous system in the usual therapeutic doses. It is related structurally to the amphetamines and is marketed as an anorectic.
    B) The drug appears to depress appetite in a manner similar to amphetamines and produces indirect alpha, beta-adrenergic action though it is 10 to 20 times less potent than amphetamines, and produces CNS depression rather than stimulation.
    C) It has little effect in normal doses upon the cardiovascular system and has been given to patients with hypertension.
    D) Fenfluramine appears to have no euphoric effects associated with high doses.
    E) ANIMALS - Monkeys given dexfenfluramine for 2 weeks developed a reduced number of 5-HT uptake sites. It was assumed that dexfenfluramine damages central 5-HT neurons (Ricaurte et al, 1991). Similar results have been seen in mice given fenfluramine (Wagner & Peroutka, 1990).

Toxicologic Mechanism

    A) In a human cell line culture, d-fenfluramine was found to be cytotoxic to the serotonin transporter expressing human placental choriocarcinoma cells, causing DNA fragmentation and apoptosis, a possible mechanism associated with human toxicity (Bengel et al, 1998).
    B) ANIMALS - In rat brain, fenfluramine was found to be a 5-HT transporter substrate. The authors speculate that because 5-HT transporter proteins are present in the lung, this may result in accumulation there and be part of the mechanism in the development of pulmonary hypertension (Rothman et al, 1999).

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