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ZOTEPINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Zotepine, a dibenzothiepine derivative, is a tricyclic antipsychotic and atypical neuroleptic agent structurally similar to clozapine, with additional 5-HT2 blocking properties.

Specific Substances

    1) 2-((8-Chlordibenzo(b,f)thiepin-1-yl)oxy)-
    2) N,N-dimethylethylamine
    3) (2-chloro-11-(2-dimethylaminoethoxy)) dibenzo(b,f) thiepine
    4) Ethanamine, 2-(8-chlorodibenzo(b,f)thiepin-10-yl)-
    5) N,N-dimethyl
    6) FR 1314
    7) Zotepin
    8) Zotepina
    9) Zotepinum
    10) CAS 26615-21-4
    11) Molecular Formula: C18-H18-Cl-N-O-S

Available Forms Sources

    A) FORMS
    1) Zotepine is available in Europe and Japan as a 25 mg, 50 mg and 100 mg tablet.
    2) Trade names include: Lodopin(R) and Nipolept(R)
    B) USES
    1) Zotepine is a tricyclic neuroleptic agent used for the treatment of manic depressive psychosis or manic schizoaffective psychosis (Hollister, 1994; (Harada & Otsuki, 1986).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Zotepine, an atypical antipsychotic drug, was used for acute and chronic schizophrenia. It is not approved for use in the United States, United Kingdom, Australia, Canada or New Zealand.
    B) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Adverse events reported at higher doses of zotepine include extrapyramidal reactions, dysarthria, EEG abnormalities and possible seizures, somnolence, dizziness, and anticholinergic effects (ie, dry mouth, constipation and urinary retention).
    C) WITH POISONING/EXPOSURE
    1) OVERDOSE: Information is limited. Overdoses may result in anticholinergic effects of dry mouth, constipation and urinary disturbances. Large overdoses may result in spontaneous vomiting. Tachycardia, hypotension and dysrhythmias may occur in overdose. Elevated liver enzymes have occurred during clinical trials and may occur following overdose. Seizures may occur with zotepine poisoning.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Tachycardia, hypotension and dysrhythmias may occur in overdose.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) At higher doses, dysarthria, somnolence and dizziness are the most frequently reported adverse effects.
    B) WITH POISONING/EXPOSURE
    1) Seizures may occur with zotepine poisoning.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Overdoses may result in anticholinergic effects of dry mouth, constipation and urinary disturbances. Large overdoses may result in spontaneous vomiting.
    0.2.9) HEPATIC
    A) WITH POISONING/EXPOSURE
    1) Liver enzyme elevation has occurred in clinical trials and may occur following overdoses.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Urinary retention, an anticholinergic effect, may occur following overdoses.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess teratogenicity or other reproductive effects in humans.
    B) Some laboratory animal studies have shown increased neonatal mortality, alveolar proliferation, enlarged breasts and galactorrhea.
    0.2.21) CARCINOGENICITY
    A) No carcinogenic effects have been reported following long-term carcinogenicity studies in animals at the time this drug was approved for use in Germany (Fachinformation, 1996).

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Treatment is symptomatic and supportive. Limited overdose information. HYPOTENSION: Administer IV fluids and place in Trendelenburg position. In theory agents with beta adrenergic activity such as epinephrine or dopamine may worsen hypotension in the setting of zotepine-induced alpha blockade. If hypotension is unresponsive to IV fluids, agents with alpha adrenergic effects such as norepinephrine or phenylephrine may be preferred. SEIZURES: Administer a benzodiazepines as needed. Initial treat with diazepam or lorazepam. Consider phenobarbital or propofol if seizures recur after diazepam. DYSTONIC REACTIONS: ADULT: BENZTROPINE: 1 to 4 mg once or twice daily IV or IM (max; 6 mg/day); 1 to 2 mg of the injection will usually provide quick relief in emergency situations, or DIPHENHYDRAMINE: ADULT: 10 to 50 mg IV at a rate not exceeding 25 mg/minute or deep IM (max; 100 mg/dose; 400 mg/day). CHILD: Diphenhydramine: 5 mg/kg/day or 150 mg/m(2)/day IV divided into 4 doses at a rate not to exceed 25 mg/min, or deep IM (max; 300 mg/day). Not recommended in premature infants and neonates. DYSRHYTHMIAS: Treat ventricular tachyarrhythmias with lidocaine followed by pacing if needed. NEUROLEPTIC MALIGNANT SYNDROME: Neuroleptic malignant syndrome may be a possible result of zotepine poisoning due to its neuroleptic activity. May be successfully managed with diphenhydramine, oral bromocriptine, benzodiazepines, or intravenous or oral dantrolene sodium in conjunction with cooling and other supportive care.
    B) DECONTAMINATION
    1) Do NOT induce emesis due to the possibility of seizures, dystonic reactions or CNS depression following overdose. Spontaneous vomiting may occur following a large overdose. Consider activated charcoal following a recent ingestion in which the airway is protected and the patient is not vomiting.
    C) ENHANCED ELIMINATION
    1) Extracorporeal methods of elimination are not likely to be of benefit in treating zotepine overdose due to extensive protein binding (97%) and a large volume of distribution.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC USE: Doses up to 450 mg/day have been used in clinical practice.

Laboratory Monitoring

    A) Monitor blood pressure for hypotensive reaction.
    B) Obtain baseline ECG and monitor for possible prolonged QT interval, conduction defects, tachycardia and/or arrhythmias. Continuous cardiac monitoring may be indicated.
    C) Monitor for akathisia and possible extrapyramidal effects.
    D) Monitor for increased plasma liver enzymes.

Clinical Effects

Summary Of Exposure

    A) USES: Zotepine, an atypical antipsychotic drug, was used for acute and chronic schizophrenia. It is not approved for use in the United States, United Kingdom, Australia, Canada or New Zealand.
    B) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Adverse events reported at higher doses of zotepine include extrapyramidal reactions, dysarthria, EEG abnormalities and possible seizures, somnolence, dizziness, and anticholinergic effects (ie, dry mouth, constipation and urinary retention).
    C) WITH POISONING/EXPOSURE
    1) OVERDOSE: Information is limited. Overdoses may result in anticholinergic effects of dry mouth, constipation and urinary disturbances. Large overdoses may result in spontaneous vomiting. Tachycardia, hypotension and dysrhythmias may occur in overdose. Elevated liver enzymes have occurred during clinical trials and may occur following overdose. Seizures may occur with zotepine poisoning.

Vital Signs

    3.3.3) TEMPERATURE
    A) HYPOTHERMIA
    1) Hypothermia is not reported alone with zotepine, however, hypothermia may result when it is combined with other neuroleptics. Noto et al (1987) reported a case of hypothermia in a patient taking zotepine, biperiden and fluphenazine. The hypothermia resulted after the addition of fluphenazine to the therapy.
    B) WITH POISONING/EXPOSURE
    1) HYPERTHERMIA
    a) Hyperthermia is more likely to occur in overdose, probably due to a decreased release of dopamine in the striatum (Dilsaver, 1988).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Because zotepine has some anticholinergic properties effects such as mydriasis, accommodation abnormalities with blurred vision may occur.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachycardia, hypotension and dysrhythmias may occur in overdose.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia, hypotension, and orthostatic hypotension have been reported following therapeutic use of zotepine in clinical trials (Tanaka et al, 1998; Fachinformation, 1996).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Electrocardiogram changes have included repolarization disturbances (prolonging QT interval) (S Sweetman , 2002; Fachinformation, 1996).
    C) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) Palpitations occurred in 11% of 28 patients treated with zotepine for 4 weeks (Kondo et al, 1994).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea has been reported in clinical trials of zotepine (Fachinformation, 1996).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) At higher doses, dysarthria, somnolence and dizziness are the most frequently reported adverse effects.
    B) WITH POISONING/EXPOSURE
    1) Seizures may occur with zotepine poisoning.
    3.7.2) CLINICAL EFFECTS
    A) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) Parkinsonian symptoms, including dystonia, rigidity, tremor, and akathisia, appear to be common and have been reported at higher doses in clinical trials (Harada & Otsuki, 1986; Kondo et al, 1994). Extrapyramidal effects have been reported at lower doses (94.4 mg/kg) (Wetterling & Mussigbrodt, 1999) (Tanaka et al, 1998).
    b) In one trial, 80% of (lithium-free) patients experienced extrapyramidal symptoms (Harada & Otsuki, 1986) and dysarthria was the most frequently reported symptom in all patients. Symptoms abated after dose reductions.
    c) Reversible akinesia with rigidity, associated with zotepine therapy, occurred in several parkinsonian patients whose symptoms had previously been controlled by dopaminergic agents (Arnold et al, 1994; Spieker et al, 1995).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported in human clinical trials, especially at higher doses (Hori et al, 1992).
    b) Up to 17% of patients in one study had reported seizures, which were more predominant in previous head trauma patients and patients on combinations of high dose zotepine with phenothiazines (Hori et al, 1992).
    C) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Although not yet reported following an overdose, neuroleptic malignant syndrome may be a possible result of zotepine poisoning due to its neuroleptic activity (Dilsaver, 1988). This syndrome may result in hyperthermia, rigors, akinesia, altered mental status, and possibly coma (Fachinformation, 1996).
    D) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) Sleepiness, asthenia, orthostatic dizziness, concentration impairment, memory loss, and depression, which abated on dose reduction, have been reported in clinical trials (Harada & Otsuki, 1986; Kondo et al, 1994).
    E) ELECTROENCEPHALOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Electroencephalogram (EEG) abnormalities, including paroxysmal discharges, have been reported (Harada & Otsuki, 1986).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) GAIT ABNORMAL
    a) DOGS: Abnormal quietness and abnormal gait were reported in a subacute and chronic toxicity study of zotepine in doses up to 64 mg/kg (Fukuhara et al, 1979).
    2) CNS DEPRESSION
    a) RATS: Oral doses of 250 mg/kg resulted in general depression in all animals in an acute toxicity study, with death resulting in all the females and in 7 of the males (Fukuhara et al, 1979).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Overdoses may result in anticholinergic effects of dry mouth, constipation and urinary disturbances. Large overdoses may result in spontaneous vomiting.
    3.8.2) CLINICAL EFFECTS
    A) PARASYMPATHOLYTIC POISONING
    1) WITH THERAPEUTIC USE
    a) Anticholinergic effects of zotepine reported in clinical trials have included dry mouth and constipation, which were dose related (Tanaka et al, 1998; Kondo et al, 1994; Harada & Otsuki, 1986).
    b) In a study of 28 schizophrenic patients treated with zotepine 100 mg/day for 1 week and 200 mg/day for 3 weeks, constipation occurred in 46%, hypersalivation in 14%, and dry mouth in 43% (Kondo et al, 1994).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) VOMITING
    a) DOGS: All dogs given a single 1000 mg/kg dose survived, probably due to spontaneous vomiting which occurred within 20 to 30 minutes after dosing (Fukuhara et al, 1979).

Hepatic

    3.9.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Liver enzyme elevation has occurred in clinical trials and may occur following overdoses.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Transient increases in liver enzyme levels have been reported in clinical trials of zotepine, up to 3 times the upper limit of normal in one study with doses up to 300 mg/day (Petit et al, 1996).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC ENZYMES INCREASED
    a) Reversible liver dysfunction, with increases in serum liver enzyme levels, occurred in a dog given 64 mg/kg/day in a 6 month study of toxicological effects of zotepine (Fukuhara et al, 1979).

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Urinary retention, an anticholinergic effect, may occur following overdoses.
    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) Urinary retention, an anticholinergic effect, has been reported at higher doses in clinical trials (Harada & Otsuki, 1986).
    2) WITH POISONING/EXPOSURE
    a) Urinary retention, an anticholinergic effect, has been reported at higher doses in clinical trials (Harada & Otsuki, 1986) and may be expected in poisonings.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Only infrequent changes in blood profile, such as leukopenia, leukocytosis, anemia, thrombocytopenia and eosinophilia have been reported in premarketing clinical trials. Agranulocytosis has not been reported with zotepine in premarketing studies (Fachinformation, 1996).
    B) THROMBOEMBOLUS
    1) WITH THERAPEUTIC USE
    a) Pantel et al (1997) described 2 cases of deep vein thrombosis associated with combined zotepine (150 mg/day) and paroxetine (40 mg/day) therapy, in the absence of common risk factors. Symptoms began on day 3 and day 17, respectively, of the combined therapy. Increased prothrombin time was noted in each case. A definite causal relationship was not established (Pantel et al, 1997).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess teratogenicity or other reproductive effects in humans.
    B) Some laboratory animal studies have shown increased neonatal mortality, alveolar proliferation, enlarged breasts and galactorrhea.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Fukuhara et al (1979) reported no adverse effects on pregnant animals (rats and rabbits) or their fetuses in an acute and chronic toxicity study of zotepine. Increased neonatal mortality was reported in animal studies at doses of 8 to 16 mg/kg (Fachinformation, 1996). There is no data concerning teratogenicity for human exposures at this time.
    2) ALVEOLAR PROLIFERATION - RATS - Dose dependent (with doses of 16 mg/kg or higher) increases in alveolar proliferations in the mammary gland were reported in subacute and chronic toxicity studies (Fukuhara et al, 1979).
    3) ENLARGED BREASTS/GALACTORRHEA - FEMALE DOGS - Doses of 16 and 64 mg/kg/day, in a 6 month study, resulted in enlarged breasts and galactorrhea (Fukuhara et al, 1979).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) No carcinogenic effects have been reported following long-term carcinogenicity studies in animals at the time this drug was approved for use in Germany (Fachinformation, 1996).

Genotoxicity

    A) In-vitro and in-vivo mutagenic tests showed no mutagenicity of zotepine (Fachinformation, 1996).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood pressure for hypotensive reaction.
    B) Obtain baseline ECG and monitor for possible prolonged QT interval, conduction defects, tachycardia and/or arrhythmias. Continuous cardiac monitoring may be indicated.
    C) Monitor for akathisia and possible extrapyramidal effects.
    D) Monitor for increased plasma liver enzymes.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) LIVER FUNCTION - Elevations of serum aspartate and alanine aminotransferases and gamma-glutamyl transferase (GGT) have been reported during zotepine therapy and may be expected in overdoses (Fachinformation, 1996).
    2) Therapeutic drug monitoring may not be helpful since there appears to be a lack of close correlation between serum drug levels and clinical or adverse effects of zotepine (Ishida, 1993; Kondo et al, 1994).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain baseline ECG to monitor for prolonged QT interval or conduction defects. Continuous monitoring of electrocardiogram is recommended following a substantial overdose due to the potential for tachyarrhythmias (Fachinformation, 1996).

Methods

    A) CHROMATOGRAPHY
    1) Ulrich et al (1996) described a capillary gas-liquid chromatographic method for the quantification of zotepine in human serum or plasma. Tokunaga et al (1996) described a wide-bore capillary gas chromatography with nitrogen phosphorus detection for the quantification of zotepine in plasma. The data from this method has been used for a rapid forensic diagnosis.
    2) Tanaka et al (1996) described a solid-phase extraction and gas chromatography-mass spectrometry (GC-MS) method for the determination of zotepine in human plasma. Detection limit of zotepine using this method is 1 mcg/L.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor blood pressure for hypotensive reaction.
    B) Obtain baseline ECG and monitor for possible prolonged QT interval, conduction defects, tachycardia and/or arrhythmias. Continuous cardiac monitoring may be indicated.
    C) Monitor for akathisia and possible extrapyramidal effects.
    D) Monitor for increased plasma liver enzymes.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Do NOT induce emesis due to the possibility of seizures, dystonic reactions or CNS depression following overdoses. Spontaneous vomiting may occur following large overdoses.
    B) 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. Limited overdose information. Zotepine is not available in the US.
    B) MONITORING OF PATIENT
    1) Monitor patients for elevated liver enzymes, tachycardia, and antimuscarinic effects.
    C) HYPOTENSIVE EPISODE
    1) Administer IV fluids and place in Trendelenburg position. In theory, agents with beta adrenergic activity such as epinephrine or dopamine may worsen hypotension in the setting of zotepine-induced alpha blockade. If hypotension is unresponsive to IV fluids, agents with alpha adrenergic effects such as norepinephrine or phenylephrine may be preferred.
    2) 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).
    3) PHENYLEPHRINE: In order to rapidly raise blood pressure, a continuous intravenous infusion of 100 to 180 micrograms/minute should be started. If an initial pressor response is not attained, adjust the rate of flow upwards until a desired blood pressure level is obtained. Titrate down to a maintenance dose of 40 to 60 micrograms/minute when blood pressure stabilizes (Prod Info Neo-Synephrine(R), phenylephrine, 1996).
    D) 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).
    E) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    F) NEUROLEPTIC MALIGNANT SYNDROME
    1) Neuroleptic malignant syndrome may be a possible result of zotepine poisoning due to its neuroleptic activity.
    2) May be successfully managed with diphenhydramine, oral bromocriptine, benzodiazepines, or intravenous or oral dantrolene sodium in conjunction with cooling and other supportive care (May et al, 1983; Mueller et al, 1983; Leikin et al, 1987; Schneider, 1991; Barkin, 1992).

Enhanced Elimination

    A) SUMMARY
    1) Methods such as forced diuresis, hemodialysis, hemoperfusion, and exchange transfusion are not likely to be of benefit in treating zotepine overdose due to extensive protein binding (97%) and a volume of distribution of approximately 10 L/kg (Fachinformation, 1996).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC USE: Doses up to 450 mg/day have been used in clinical practice.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Usual dose for schizophrenic psychoses is 75 to 150 milligrams/day in divided doses. As an inpatient, a maximum dose of 450 milligrams/day may be given in divided doses, at least 4 hours apart (Fachinformation, 1996).
    2) SPECIAL CONSIDERATIONS -
    a) LIVER DYSFUNCTION - Maximum daily dose should not exceed 300 milligrams/day in divided doses in patients with mild to moderate liver dysfunction, and liver function should be monitored (Fachinformation, 1996).

Maximum Tolerated Exposure

    A) SUMMARY
    1) Overdose information was not available at the time of this review. Anticholinergic effects, which were dose related, occurred at the upper limit of normal doses in clinical trials (Kondo et al, 1994; Harada & Otsuki, 1986).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ADULT
    a) Zotepine concentrations associated with therapeutic dosing range from 5 to 317 nanograms/milliliter (Tokunaga et al, 1996).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ADULT
    a) POSTMORTEM - Heart blood collected 2 days postmortem from a 46-year-old male, who had been given large amounts of antipsychotics, was analyzed and showed a toxic zotepine concentration of 0.61 micrograms/milliliter (Tokunaga et al, 1996).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 108 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)RAT:
    a) 306 mg/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Zotepine, a tricyclic neuroleptic, has a dibenzothiepine structure, similar to clozapine and phenothiazines, with both sedative and antipsychotic effects. It has dopamine-D2, serotonin-5HT2 and alpha-1-adrenergic receptor antagonistic effects and weak anticholinergic effects.
    1) Its neuroleptic activity is a result of dopamine receptor blockade, particularly at post-synaptic dopamine receptors. Dopamine-D2 mediated effects include stereotypical behavior, psychotic symptoms, and emesis.
    2) Zotepine preferentially blocks mesolimbic dopamine-D2 receptors and to a lesser extent the nigrostriatal receptors which are responsible for unwanted extrapyramidal effects. Antiserotonergic action may also contribute to its neuroleptic effects (Fricke & Klaus, 1991).
    3) Zotepine has affinities for both cloned human D1 and D2 receptors, which are similar, and probably responsible for its reduced incidence of extrapyramidal side effects, as compared to clozapine, which shows an imbalance favoring D1 over D2 receptors (Needham et al, 1996).
    4) Zotepine was shown to have a lower affinity and antagonistic potency at H3 receptors than did clozapine in a rat study (Schlicker & Marr, 1996).
    B) In animal studies, zotepine does not appear to affect 5-HT1A or 5-HT1C receptors. It slightly inhibits 5-HT1B receptors (Czyrak et al, 1994). Low doses of zotepine decrease serum prolactin levels by 80%, while high doses increase serum prolactin levels, probably as a result of the antidopaminergic properties. In vitro, the potential for zotepine to induce orthostatic hypotension is approximately the same as other neuroleptics, while its cardiac adverse effects are somewhat weaker (Uchida et al, 1979).
    C) Zotepine has been shown to possess antiemetic actions in animal studies (Fricke & Klaus, 1991).

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