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VILOXAZINE AND RELATED DRUGS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Zimeldine and viloxazine are bicyclic antidepressants which have selective serotonin reuptake inhibitor activity.

Specific Substances

    A) VILOXAZINE
    1) 2-((2-ethoxyphenoxy)methyl)morpholine
    2) 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine
    3) ICI-58834
    4) CAS 46817-91-8 (viloxazine)
    5) CAS 35607-67-2 (viloxazine hydrochloride)
    ZIMELDINE
    1) (Z)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridinyl)-2
    2) -propen-1-amine
    3) (Z)-3-(4-bromophenyl)-3-(3''-pyridyl)methylallyamine
    4) CAS 56775-88-3 (zimeldine)
    5) CAS 60525-15-7 (anhydrous zimeldine dihydrochloride)
    6) CAS 61129-30-4 (zimeldine dihydrochloride monohydrate)

Available Forms Sources

    A) FORMS
    1) VILOXAZINE - Trade Name: Vivalan
    B) USES
    1) Zimeldine and viloxazine are bicyclic antidepressants.
    2) Zimeldine was withdrawn from the world-wide market in 1983 due to the risk of development of Guillain-Barre syndrome associated with its use.

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Compared with tricyclics, bicyclic antidepressants appear to have a lower incidence of cardiovascular and anticholinergic toxicity.
    1) VILOXAZINE - Drowsiness, decreased reflexes, miosis, hypotension, and tachycardia may occur in viloxazine overdose.
    2) ZIMELDINE was withdrawn from the world-wide market in 1983 due to the risk of development of Guillain-Barre syndrome associated with its use. Seizures occurred in 2 patients who overdosed on zimeldine.
    0.2.3) VITAL SIGNS
    A) ZIMELDINE - Fever may occur with therapeutic doses of zimeldine.
    0.2.4) HEENT
    A) Miosis and blurred vision have occurred with viloxazine therapeutic use.
    0.2.5) CARDIOVASCULAR
    A) Viloxazine has produced electrocardiogram disturbances, orthostatic hypotension, hypertension, palpitations, and tachycardia.
    B) Zimeldine has caused decreased heart rate and prolongation of the QT interval, and torsade de pointes.
    0.2.7) NEUROLOGIC
    A) Viloxazine may cause seizures, headache, somnolence, dizziness, drowsiness, insomnia, numbness, or tingling.
    B) Zimeldine may cause headache, insomnia, extrapyramidal syndrome, or neuropathy. Zimeldine was withdrawn from the market due to the development of Guillain-Barre syndrome. Seizures occurred in 2 patients who overdosed on zimeldine.
    0.2.8) GASTROINTESTINAL
    A) Viloxazine therapeutic use has been associated with nausea, vomiting, epigastric pain, dry mouth, diarrhea, and anorexia.
    B) Nausea, dry mouth, constipation, and anorexia have occurred with zimeldine therapeutic use.
    0.2.9) HEPATIC
    A) Zimeldine use has resulted in transient elevations of liver enzymes. One case of hepatocellular jaundice and fever has been reported with zimeldine use.
    0.2.10) GENITOURINARY
    A) Micturition difficulties have occurred with viloxazine therapy.
    0.2.14) DERMATOLOGIC
    A) Stevens-Johnson syndrome has occurred with zimeldine use.
    0.2.15) MUSCULOSKELETAL
    A) Myalgia and elevated creatine phosphokinase occurred during zimeldine treatment.
    0.2.17) METABOLISM
    A) Zimeldine and viloxazine have been associated with weight loss.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no human data were available to assess the potential effects of exposure to these drugs during pregnancy or lactation. Studies in the rat model have suggested subtle behavior changes in offspring of treated rats.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.

Laboratory Monitoring

    A) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.

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) 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.
    C) PVCS/SUMMARY: Treatment of PVCs may include lidocaine, or overdrive transvenous pacing. Atropine may be used when severe bradycardia is present and PVCs are thought to represent an escape complex.
    D) TORSADES DE POINTES: Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    1) MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes. An optimal dose has not been established. Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram/hour, if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 minutes.
    2) OVERDRIVE PACING: Begin at 130 to 150 beats per minute, decrease as tolerated.
    3) Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.

Range Of Toxicity

    A) Zimeldine overdoses of 0.5 and 2 grams caused seizures, adult survived a 5 g zimeldine ingestion.
    B) Ingestions of viloxazine ranging from 100 mg to 4 g have resulted in seizures and loss of consciousness with full recovery.

Clinical Effects

Genitourinary

    3.10.1) SUMMARY
    A) Micturition difficulties have occurred with viloxazine therapy.
    3.10.2) CLINICAL EFFECTS
    A) DYSURIA
    1) VILOXAZINE - Micturition difficulties have occurred with viloxazine therapy (Floru et al, 1976).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) ZIMELDINE - Mild decreases in white blood cell counts affecting all cell lines and mild thrombocytopenia have been reported with zimeldine therapy (Langlois et al, 1985).

Dermatologic

    3.14.1) SUMMARY
    A) Stevens-Johnson syndrome has occurred with zimeldine use.
    3.14.2) CLINICAL EFFECTS
    A) STEVENS-JOHNSON SYNDROME
    1) CASE REPORT (ZIMELDINE) - Schweizer et al (1985) reported a case of severe Erythema Multiforme (Stevens-Johnson Syndrome) secondary to zimeldine therapy in a 69-year-old woman following 2 doses of the drug.

Musculoskeletal

    3.15.1) SUMMARY
    A) Myalgia and elevated creatine phosphokinase occurred during zimeldine treatment.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) ZIMELDINE - Myalgia and elevated creatine phosphokinase occurred during zimeldine treatment (Pomara et al, 1984; Langlois et al, 1985).

Immunologic

    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LYMPHEDEMA
    a) ZIMELDINE - When administered orally to rats in an 8 week study, lipidosis-like cellular alterations occurred in the lymph nodes and adrenal cortex, which were reversible on drug withdrawal (Davies, 1998).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no human data were available to assess the potential effects of exposure to these drugs during pregnancy or lactation. Studies in the rat model have suggested subtle behavior changes in offspring of treated rats.
    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.
    3.20.3) EFFECTS IN PREGNANCY
    A) HUMANS
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    B) ANIMAL STUDIES
    1) Studies in the rat model have suggested that doses which do not influence reproductive success or neonatal mortality produce subtle behavior changes in offspring of treated rats (Cuomo et al, 1984).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Viloxazine is excreted into breast milk and is not recommended in patients who are breast feeding.

Summary Of Exposure

    A) Compared with tricyclics, bicyclic antidepressants appear to have a lower incidence of cardiovascular and anticholinergic toxicity.
    1) VILOXAZINE - Drowsiness, decreased reflexes, miosis, hypotension, and tachycardia may occur in viloxazine overdose.
    2) ZIMELDINE was withdrawn from the world-wide market in 1983 due to the risk of development of Guillain-Barre syndrome associated with its use. Seizures occurred in 2 patients who overdosed on zimeldine.

Vital Signs

    3.3.1) SUMMARY
    A) ZIMELDINE - Fever may occur with therapeutic doses of zimeldine.

Heent

    3.4.1) SUMMARY
    A) Miosis and blurred vision have occurred with viloxazine therapeutic use.
    3.4.3) EYES
    A) VILOXAZINE -
    1) Miosis has been seen with viloxazine (Pinder et al, 1977).
    2) Blurred vision has occurred with viloxazine; however, the incidence appears to be less than that observed with tricyclic antidepressants (Petrie et al, 1982; Nair & Schwartz, 1982).

Cardiovascular

    3.5.1) SUMMARY
    A) Viloxazine has produced electrocardiogram disturbances, orthostatic hypotension, hypertension, palpitations, and tachycardia.
    B) Zimeldine has caused decreased heart rate and prolongation of the QT interval, and torsade de pointes.
    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) VILOXAZINE - Clinical studies have reported a low incidence of cardiovascular side effects with viloxazine in contrast to tricyclic antidepressants. The drug has occasionally produced electrocardiogram disturbances, orthostatic hypotension, hypertension, palpitations, and tachycardia (Floru et al, 1976; Moizeszowicz & Subira, 1977; Santonastaso et al, 1979; McEvoy et al, 1982); however, the incidence is generally less than that observed with amitriptyline (Petrie et al, 1982a; Petrie et al, 1982).
    a) Unlike tricyclic antidepressants, overdosage with viloxazine appears to produce non-life-threatening arrhythmias, as compared to the more serious refractory arrhythmias seen with tricyclic agents (Holland & Brosnan, 1979).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) ZIMELDINE may have less toxic effects on the cardiovascular system than other antidepressants. Burgess et al (1979) compared the cardiac effects of amitriptyline, zimeldine, mianserin, and nomifensine on systolic time intervals and on high speed surface EKG in depressed patients.
    a) Amitriptyline was shown to increase the pre-injection period index and PEP:LVET ratio of the systolic time interval, as well as increase heart rate and prolong QT interval.
    b) Zimeldine had no effect on systolic time interval, but did result in decreased heart rate and prolongation of the QT interval. None of the antidepressants had a significant effect upon blood pressure.
    c) The authors suggest that these properties of zimeldine would make it safer for administration to patients with known heart disease.
    C) ORTHOSTATIC HYPOTENSION
    1) ZIMELDINE - Pottage et al (1983) have reviewed the cardiovascular effects of zimeldine. In therapeutic doses, zimeldine produces no significant impairment of myocardial contractility or conduction. Postural hypotension has occurred, although it is not common.
    a) The authors concluded that the risk of cardiovascular toxicity are much less than that observed with tricyclic antidepressants (blood pressure changes, conduction defects, prolonged repolarization and arrhythmias).
    D) TORSADES DE POINTES
    1) CASE REPORT (ZIMELDINE) - A 65-year-old female ingested 500-600 mg zimeldine and 40-50 mg flunitrazepam and was brought to the emergency department the following morning. EKG showed sinus rhythm with supraventricular extrasystoles and frequent episodes of ventricular tachycardia with torsade de pointes morphology. The QT time was significantly prolonged and the QRS interval was 0.12 seconds. The tachycardia resolved with lidocaine administration (Liljeqvist & Edvardsson, 1989).

Respiratory

    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DYSPNEA
    a) ZIMELDINE - When administered orally to rats in an 8 week study, zimeldine was shown to cause lipidosis-like cellular alterations in the lungs, resulting in dyspnea and lung dysfunction which were reversible on drug withdrawal (Davies, 1998).

Neurologic

    3.7.1) SUMMARY
    A) Viloxazine may cause seizures, headache, somnolence, dizziness, drowsiness, insomnia, numbness, or tingling.
    B) Zimeldine may cause headache, insomnia, extrapyramidal syndrome, or neuropathy. Zimeldine was withdrawn from the market due to the development of Guillain-Barre syndrome. Seizures occurred in 2 patients who overdosed on zimeldine.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) VILOXAZINE -
    a) Seizures have occurred during viloxazine therapy (Edwards, 1977; Edwards, 1977a) and following overdose (Falcy et al, 1983). Seizures are less likely following a viloxazine overdose than a tricyclic antidepressant overdose (S Sweetman , 2001).
    b) CASE SERIES - Edwards & Glen-Bott (1984) reported 6 cases of seizures during viloxazine treatment that were reported to the Committee on Safety of Medicine in the UK, and 2 other reports from Japan. Review of these patients' histories suggested a possible causal relationship in only 2 of the patients (S Sweetman , 2001).
    1) The incidence of seizures occurring with viloxazine was approximately 0.01%, less than that observed with imipramine and amitriptyline, and viloxazine would not be contraindicated in epileptic patients requiring antidepressants. However, more studies are required to evaluate the incidence of seizures.
    B) HEADACHE
    1) VILOXAZINE -
    a) Headaches have occurred in up to one-half of patients treated (Petrie et al, 1980; McEvoy et al, 1982; Barnes et al, 1979), with the incidence being higher than that seen with tricyclic antidepressants in some reports. Migraine headaches have occurred (Barnes et al, 1979).
    b) Headaches occurred in 50% of 30 patients treated with viloxazine 150 to 300 mg daily in one study (Barnes et al, 1979). Five of these patients suffered a migraine-like syndrome with nausea in the absence of a history of migraine headaches. These symptoms did not occur after withdrawal of viloxazine.
    1) An 18-year-old woman had severe left supraorbital headache after 5 days of viloxazine treatment, accompanied by nausea and visual disturbances. Withdrawal of viloxazine resulted in subsidence of symptoms.
    2) Viloxazine may have the propensity of inducing migraine headaches by its effect on inhibiting norepinephrine reuptake in both central and peripheral nervous tissue and potentiating certain effects of serotonin, probably by a presynaptic-releasing action. These effects could induce cerebrovascular vasoconstriction and lead to side effects of migraine.
    2) ZIMELDINE - Headache has been reported during zimeldine therapy (Sommerville et al, 1982; Evans et al, 1980) Langolis et al, 1985).
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) VILOXAZINE - Somnolence, dizziness, drowsiness, insomnia, numbness, and tingling have occurred with viloxazine (Petrie et al, 1982a; Petrie et al, 1982; Petrie et al, 1980; McEvoy et al, 1982; Nair & Schwartz, 1982; Battistini et al, 1980). Transitory loss of consciousness with recovery within a few hours has been reported after viloxazine overdoses (Falcy et al, 1983).
    2) INCIDENCE - The overall incidence of CNS adverse effects appears less than that observed with other antidepressants in some studies; however, other investigators have reported a similar incidence of CNS side effects, primarily drowsiness, dizziness, and headache (Wheatley, 1974; McEvoy et al, 1982).
    3) Tremor has occurred with viloxazine (Floru et al, 1976), although the incidence appears less than that seen with tricyclic antidepressants. Other CNS effects have been vertigo, confusion, hypomanic episodes, and sleep disturbances (Floru et al, 1976).
    D) GUILLAIN-BARRé SYNDROME
    1) ZIMELDINE - Thirteen cases of Guillain-Barre syndrome were reported within 1 and 1/2 years of introduction of the drug in Sweden. The risk of developing Guillain-Barre syndrome appeared to increase 25-fold among patients taking zimeldine (Fagius et al, 1985)
    E) INSOMNIA
    1) ZIMELDINE - Difficulty in sleeping has been reported during zimeldine therapy. Simpson et al (1980) reported that INSOMNIA was significantly greater in patients receiving zimeldine than placebo in a double-blind randomized trial involving 24 obese patients without psychiatric illness.
    F) NEUROPATHY
    1) ZIMELDINE - Neuropathy was reported in 2 patients receiving zimeldine during the first week of treatment. Neuropathy resolved in both patients several months after discontinuing zimeldine (Dexter, 1984).
    G) EXTRAPYRAMIDAL DISEASE
    1) Viloxazine (Falcy et al, 1983) and zimeldine (Ansseau et al, 1985) have been reported to produce extrapyramidal syndrome following overdose.
    2) CASE REPORT (ZIMELDINE) - A 35-year-old woman exhibited a distinct extrapyramidal syndrome following zimeldine 5-gram overdose. Signs included marked parkinsonian tremor and cogwheel rigidity. Her consciousness was not altered and serial ECGs showed only a slight increase in QT duration (Ansseau et al, 1985).

Gastrointestinal

    3.8.1) SUMMARY
    A) Viloxazine therapeutic use has been associated with nausea, vomiting, epigastric pain, dry mouth, diarrhea, and anorexia.
    B) Nausea, dry mouth, constipation, and anorexia have occurred with zimeldine therapeutic use.
    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) VILOXAZINE - Nausea, vomiting, epigastric pain, and diarrhea are fairly common side effects of viloxazine therapy, occurring much more frequently as compared with tricyclic antidepressants (Petrie et al, 1982a; Petrie et al, 1982; Petrie et al, 1980; Floru et al, 1976; Ban et al, 1980).
    a) INCIDENCE - The overall incidence of nausea was approximately 19%; vomiting occurred in 5% of 771 consecutive patients treated. The dropout rate in clinical trials due to both nausea and vomiting was about 7% (Ban et al, 1980).
    2) ZIMELDINE - Nausea, diarrhea, and abdominal pain developed in 4 of 15 patients taking therapeutic doses of zimeldine (Langlois et al, 1985).
    B) APTYALISM
    1) VILOXAZINE -
    a) Dry mouth occurs during viloxazine therapy, although with the incidence being less than that seen with tricyclic antidepressants in some studies (Petrie et al, 1980; Davies et al, 1977; Nair & Schwartz, 1982; Kiloh et al, 1979).
    b) Other reports have indicated a similar or greater incidence of dry mouth occurring in viloxazine-treated patients as compared to amitriptyline or imipramine (McEvoy et al, 1982; Petrie et al, 1982; Petrie et al, 1982a). Wheatley (1974) reported a similar incidence of dry mouth and other side effects with imipramine and viloxazine.
    2) ZIMELDINE - Oral administration of zimeldine has been associated with nausea and dryness of the mouth (Benkert et al, 1977). Georgotas et al (1980) administered zimeldine 75 to 300 mg daily for a period of 4 weeks to 10 patients with depression. Four patients developed dryness of the mouth and 2 other patients developed constipation.
    C) WEIGHT LOSS FINDING
    1) VILOXAZINE - Weight loss has been associated with viloxazine therapy.
    2) ZIMELDINE - Simpson et al (1981) reported that zimeldine 100 mg BID significantly reduced appetite and induced weight loss (average, 2.5 kg) to a greater extent than placebo in an 8-week double-blind, crossover study.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.

Hepatic

    3.9.1) SUMMARY
    A) Zimeldine use has resulted in transient elevations of liver enzymes. One case of hepatocellular jaundice and fever has been reported with zimeldine use.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) ZIMELDINE - Transient increases in serum transaminase levels have been reported during zimeldine therapy (Benkert et al, 1977; Sommerville et al, 1982; Langlois et al, 1985).
    B) JAUNDICE
    1) CASE REPORT - Hepatocellular jaundice and fever were reported in a 47-year-old diabetic during treatment with zimeldine. Nine days after treatment with 100 mg PO BID and lorazepam 1 mg PRN the patient was admitted to the hospital with increasing nausea, vomiting, and lassitude. The patient was febrile and jaundiced, but did not have hepatomegaly. Serological tests did not reveal viral hepatitis.
    a) The patient was rechallenged with zimeldine in doses of 25 mg PO BID, resulting in recurrence of hepatotoxicity. On each admission, significant increases in serum bilirubin, alanine aminotransferase, lactic dehydrogenase, and alkaline phosphatase were observed.
    b) The authors suggest that the hepatic reaction to zimeldine is a hypersensitivity reaction since liver dysfunction was more severe on the second episode with administration of lower doses (Simpson & Davidson, 1983).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.

Methods

    A) CHROMATOGRAPHY
    1) Zimeldine and norzimeldine have been measured in plasma by gas chromatography (Hogberg et al, 1979) and by high pressure liquid chromatography (Emanuelsson & Moore, 1977).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Carefully observe patients with ingestion exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

Monitoring

    A) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.

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).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. Seizures may occur and should be treated aggressively. Cardiac monitoring is recommended.
    2) Physostigmine may INDUCE SEIZURES in the zimeldine or viloxazine poisoned patient and should NOT be used.
    B) 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).
    C) VENTRICULAR ARRHYTHMIA
    1) Treatment of ventricular dysrhythmias may include cardioversion, lidocaine, or overdrive transvenous pacing.
    a) VENTRICULAR DYSRHYTHMIAS SUMMARY
    1) 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).
    D) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Abstracts

Case Reports

    A) SPECIFIC AGENT
    1) ADULT
    a) ZIMELDINE - Seizures developed in a 32-year-old male approximately 4 hours after ingestion of zimeldine 2.5 g with alcohol. The patient was treated with diazepam and recovered uneventfully.
    b) ZIMELDINE - A 37-year-old female developed grand mal seizures 5 hours after ingestion of zimeldine 2 g without alcohol. The seizure lasted 45 seconds and was associated with urinary incontinence; no treatment was administered and recovery was uneventful.
    c) ZIMELDINE - No toxic symptoms were observed following an overdose of zimeldine (1.75 grams) in combination with alcohol and 5 to 6 propoxyphene capsules in one patient being treated for depression. Serum concentrations of zimeldine and norzimelidine were 600 ng/mL and 380 ng/mL, respectively. These concentrations were about 10 times greater than those obtained following administration of therapeutic doses (Georgotas et al, 1980).
    d) ZIMELDINE - Seizures developed in a patient with a family history of epilepsy following ingestion of 1.7 g with alcohol; only sedation and vomiting occurred following a 2.8 g overdose in a second patient; no toxicity was observed following 1.75 g of zimeldine in a third patient. Seizures appear to be the primary effect observed following overdose (Chapman & Proudfoot, 1983).
    e) ZIMELDINE - A 29-year-old female ingested 5.2 grams zimeldine and presented complaining of dizziness, nausea and abdominal pain. Physical exam revealed nystagmus and coarse tremor bilaterally. Cardiovascular exam showed slight PR prolongation and tachycardia (heart rate 120 beats/minute), both of which returned to normal within 8 hours. Liver function tests showed slight elevation of transaminases, although within normal range (Judd et al, 1983).

Range Of Toxicity

Summary

    A) Zimeldine overdoses of 0.5 and 2 grams caused seizures, adult survived a 5 g zimeldine ingestion.
    B) Ingestions of viloxazine ranging from 100 mg to 4 g have resulted in seizures and loss of consciousness with full recovery.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) VILOXAZINE -
    a) Usual doses in depression are 150 to 450 milligrams/day; no dose has been established for narcolepsy cataplexy (Nair & Schwartz, 1982; McEvoy et al, 1982).
    2) ZIMELDINE -
    a) In adults, effective oral doses of zimeldine used for depression are 50 to 300 milligrams/day. Doses of 100 milligrams PO BID for 14 weeks have been used to reduce the intensity and duration of migraine headache (Georgotas et al, 1980; Coppen et al, 1979; Cox et al, 1978; Aberg & Holmberg, 1979).
    b) Zimeldine was withdrawn from the world-wide market in 1983 due to the risk of development of Guillain-Barre syndrome associated with its use.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) VILOXAZINE -
    a) Falcy et al (1983) have reported viloxazine overdoses ranging from 100 milligrams to 4 grams with no deaths reported. Transient loss of consciousness in one patient, seizures in two patients and one case of extrapyramidal syndrome were the only complications reported in these cases.
    2) ZIMELDINE -
    a) An overdose of 5 grams was survived by a 35-year-old woman (Ansseau et al, 1985).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) ZIMELDINE -
    1) Peak plasma levels following a 5-gram overdose were 1985 nanograms/milliliter zimeldine and 1995 nanograms/milliliter norzimelidine (Ansseau et al, 1985).
    2) Two cases of convulsions after overdoses of zimeldine 0.5 grams and 2 grams have been reported. The peak zimeldine serum concentration levels were 4.8 mg/L and 0.7 mg/L, respectively (Chapman & Proudfoot, 1983).
    3) No significant correlation between blood levels of zimeldine (or its metabolite, norzimeldine) and frequency of side effects were reported in one study (von norring & Johansson, 1979).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) VILOXAZINE
    1) LD50- (ORAL)MOUSE:
    a) 552 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)RAT:
    a) 2 g/kg (RTECS, 2002)
    B) VILOXAZINE HYDROCHLORIDE
    1) LD50- (ORAL)MOUSE:
    a) 480 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)RAT:
    a) 2 g/kg (RTECS, 2002)
    C) ZILMELDINE HYDROCHLORIDE
    1) LD50- (ORAL)MOUSE:
    a) 341 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)RAT:
    a) 844 mg/kg (RTECS, 2002)

Physicochemical

Molecular Weight

    A) VILOXAZINE - 237.30 (Budavari, 1996)
    B) ZIMELDINE - 317.23 (Budavari, 1996)

References

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