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REBOXETINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Reboxetine is a unique, new class of antidepressant known as a potent selective norepinephrine reuptake inhibitor (NRI), or noradrenaline reuptake inhibitor (NARI) with little or no effect on serotonin reuptake. Unlike tricyclic antidepressants, it has no significant affinity for muscarinic-cholinergic receptors, histamine (H1), or adrenergic receptors.

Specific Substances

    1) FCE-20124 (reboxetine or reboxetine mesylate)
    2) PNU 155950E (reboxetine mesylate)
    3) CAS 71620-89-8 (reboxetine)
    4) CAS 98769-81-4 (reboxetine)
    5) CAS 98769-82-5 (reboxetine mesylate)
    6) CAS 08769-84-7 (reboxetine mesylate)
    7) C(19)H(23)NO(3)

Available Forms Sources

    A) USES
    1) Reboxetine was approved for use in the treatment of depression in the United States in February, 2000. In several European countries, it has been licensed in the treatment of depression (Herman et al, 1999)
    2) Reboxetine is used in the treatment of severe depression (Delgado & Michaels, 1999), and has been used in limited studies as a combination therapy for refractory depression (Fava, 2000)
    3) It has been shown to be effective in the short- and long-term treatment of depression (Denolle et al, 1999)

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Adverse effects that have been reported with therapeutic use include the following: mild hypotension or hypertension, tachycardia, mydriasis, blurred vision, constipation, dry mouth, nausea, urinary hesitancy/urgency, headache/migraines, sweating, and insomnia. Seizures and hyponatremia have been reported rarely.
    2) Based on its limited affinity for adrenergic or muscarinic-cholinergic receptors, reboxetine appears to have a low toxicity profile in clinical use, with fewer cognitive, cardiovascular, and gastrointestinal side effects than tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs).
    B) WITH POISONING/EXPOSURE
    1) There are minimal reports of overdose with this agent. No fatalities have been reported with reboxetine alone. Clinical effects in overdose are expected to be an exaggeration of known adverse events (sympathomimetic effects due to norepinephrine {NE} reuptake blockade). Seizures are theoretically possible following overdose.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Asymptomatic orthostatic hypotension, transient hypertension and tachycardia have developed with reboxetine administration. Infrequent reports of ECG changes in the elderly have occurred.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Insomnia, headache, and dizziness are the most frequently reported adverse effects with reboxetine therapy. Seizures have occurred rarely during clinical trials.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Constipation and dry mouth are common. Nausea appears to occur less frequently with therapy.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Urinary hesitancy/retention has occurred following reboxetine administration.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH THERAPEUTIC USE
    1) Hyponatremia and SIADH have been reported rarely.
    0.2.20) REPRODUCTIVE
    A) In animal studies, reboxetine was found to cross the placenta and is distributed in breast milk.

Laboratory Monitoring

    A) Monitor serum electrolytes and ECG following significant ingestion.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Treatment is SYMPTOMATIC and SUPPORTIVE.
    B) 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.
    C) 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.
    D) Monitor neurological status following a significant overdose, seizures are theoretically possible with overdose.

Range Of Toxicity

    A) There are minimal reports of overdose with this agent. No fatalities have been reported with reboxetine alone. One patient ingested 52 mg reboxetine and developed minimal toxicity; up to 240 mg have been ingested with survival reported.
    B) Overdose effects are anticipated to be an exaggeration of adverse clinical effects.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Adverse effects that have been reported with therapeutic use include the following: mild hypotension or hypertension, tachycardia, mydriasis, blurred vision, constipation, dry mouth, nausea, urinary hesitancy/urgency, headache/migraines, sweating, and insomnia. Seizures and hyponatremia have been reported rarely.
    2) Based on its limited affinity for adrenergic or muscarinic-cholinergic receptors, reboxetine appears to have a low toxicity profile in clinical use, with fewer cognitive, cardiovascular, and gastrointestinal side effects than tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs).
    B) WITH POISONING/EXPOSURE
    1) There are minimal reports of overdose with this agent. No fatalities have been reported with reboxetine alone. Clinical effects in overdose are expected to be an exaggeration of known adverse events (sympathomimetic effects due to norepinephrine {NE} reuptake blockade). Seizures are theoretically possible following overdose.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Asymptomatic supine and postural hypotension have occurred with therapeutic use, along with occasional reports of transient hypertension (Massanna, 1998; (Denolle et al, 1999; Burns, 2000).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Increases in resting heart rate have been reported with reboxetine therapy (Gutierrez et al, 1999; Denolle et al, 1999; Burns, 2000).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred vision and mydriasis have occurred during therapeutic use of reboxetine (Burns, 2000).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Asymptomatic orthostatic hypotension, transient hypertension and tachycardia have developed with reboxetine administration. Infrequent reports of ECG changes in the elderly have occurred.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Mild postural hypotension has been reported with clinical use (Mucci, 1997; Massana, 1998; M Sweetman , 2000).
    b) INCIDENCE - In 2 multicenter, double-blinded clinical studies, hypotension was reported in 13% of patients as compared to 6% of patients receiving fluoxetine therapy and were rated mild to moderate (Massana, 1998). The effects, however, were not considered clinically significant.
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Transient, mild increase in both diastolic and systolic blood pressure have been reported in volunteers receiving reboxetine therapy (Denolle et al, 1999; Burns, 2000). It is thought that these alterations are due to NE reuptake blockade in central and peripheral tissues (Burns, 2000).
    C) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Denolle et al (1999) reported in a small study of healthy male volunteers (n=9), that reboxetine was associated with transient increases in heart rate (from a baseline of 50 to 80 bpm increasing to 60 to 96 bpm), which occurred at 1 to 1 1/2 hours after administration. The effects lasted for 7 to 8 hours peaking at 3 to 4 hours for supine and 3 to 8 hours for standing position.
    b) INCIDENCE - In a review of various clinical trials (n=1503) using reboxetine, 6% of patients developed tachycardia (Gutierrez et al, 1999).
    D) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In clinical studies, elderly patients receiving reboxetine were more likely to experience conduction disturbances, tachycardia, and occasional atrial and ventricular ectopy (Mucci, 1997).
    b) LACK OF EFFECT -
    1) In a study of 20 healthy volunteers, using a 5 way cross over design (placebo, 2 mg, 4 mg, 6 mg reboxetine and 6 mg reboxetine with 200 mg ketoconazole) no statistically significant prolongation of the QTc occurred (Fleishaker et al, 2001).
    2) In a small study of healthy, male volunteers, no alteration in ECG parameters were reported with therapeutic dosing (Denolle et al, 1999).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Insomnia, headache, and dizziness are the most frequently reported adverse effects with reboxetine therapy. Seizures have occurred rarely during clinical trials.
    3.7.2) CLINICAL EFFECTS
    A) WAKEFULNESS FINDING
    1) WITH THERAPEUTIC USE
    a) In clinical trials, reboxetine appears to have less psychomotor and cognitive effects (no sedation) than TCAs (Herrmann & Fuder, 1998; Delgado & Michaels, 1999). In contrast, increased vigilance was observed in healthy adults given reboxetine (Herrmann & Fuder, 1998).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Headache, dizziness, and insomnia commonly developed during therapeutic use (Massana, 1998; Delgado & Michaels, 1999) Burns, 2000).
    b) INCIDENCE - In a review of clinical trials of 1503 reboxetine-treated patients, 11% of patients experienced either insomnia or headache, and 7% complained of dizziness (Gutierrez et al, 1999).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures were a rare occurrence during reboxetine therapy. In a review of 1247 reboxetine-treated patients, 2 patients (0.13%) developed seizures (Delgado & Michaels, 1999).
    2) WITH POISONING/EXPOSURE
    a) Although clinical data is lacking, theoretically, seizures may occur following reboxetine overdose since NE reuptake blockade has a role in seizures that occur with other cyclic antidepressants (e.g., TCAs, SSRIs) (Burns, 2000).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Constipation and dry mouth are common. Nausea appears to occur less frequently with therapy.
    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Reboxetine has resulted in constipation, dry mouth, and nausea following therapeutic use (Mucci, 1997; Massana, 1998) Gutierreze et al, 1999; (Burns, 2000).
    b) INCIDENCE - Dry mouth (22%) and constipation (15%) were the two most frequently reported adverse effects observed during a review of clinical studies in reboxetine-treated patients (Gutierrez et al, 1999). Nausea occurred in 8% of patients.

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Urinary hesitancy/retention has occurred following reboxetine administration.
    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) Urinary hesitancy and/or retention has occurred following treatment (Mucci, 1997) Szabadi, 1998; (Burns, 2000).
    b) INCIDENCE - In a randomized, double-blind multicenter study, urinary hesitancy and/or retention occurred in 7.7% of reboxetine-treated patients (n=130) as compared to 4.8% of imipramine-treated patients (n=126) (Berzewski et al, 1997).
    c) CASE REPORT - A 59-year-old depressed male developed urinary hesitancy and difficulty emptying the bladder completely after starting reboxetine therapy; the patient chose to stop therapy without physician knowledge (Szabadi, 1998). However, based on the patient's recurrence of depression, reboxetine was restarted with concomitant doxazosin therapy; no further urological symptoms were reported.
    1) Its suggested that reboxetine can potentiate the effects of sympathetically released noradrenaline in the urinary bladder which can inhibit the contraction of the detrusor muscle.

Reproductive

    3.20.1) SUMMARY
    A) In animal studies, reboxetine was found to cross the placenta and is distributed in breast milk.
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) In animal studies, reboxetine was found to cross the placenta (M Sweetman , 2000).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) ANIMAL STUDIES
    1) In animal studies, reboxetine is distributed in breast milk (M Sweetman , 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes and ECG following significant ingestion.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Reboxetine serum levels are not clinically useful.
    2) Obtain serum electrolytes following a significant exposure.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG following a significant ingestion.

Methods

    A) CHROMATOGRAPHY
    1) High-performance liquid chromatography (HPLC) would provide confirmation and quantitation of reboxetine in the plasma. The correlation, however, between serum reboxetine concentrations and therapeutic or toxic effects are unknown (Burns, 2000).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor serum electrolytes and ECG following significant ingestion.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) EMESIS: Ipecac-induced emesis is not recommended because there is so little information about the effects of overdose in humans.
    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).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is SYMPTOMATIC and SUPPORTIVE.
    B) MONITORING OF PATIENT
    1) Monitor vital signs including blood pressure following ingestion. Asymptomatic reports of hypotension and tachycardia have been reported with therapeutic use.
    C) 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) Norepinephrine may be more effective than an indirect acting agent such as dopamine because reboxetine inhibits norepinephrine reuptake.
    3) 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).
    4) 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).
    D) SEIZURE
    1) At the time of this review, seizures have not been reported, but are theoretically possible following overdose. Monitor neurological status following significant ingestion or as indicated.
    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).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Reboxetine is highly protein-bound, therefore it is unlikely that hemodialysis would be effective.

Range Of Toxicity

Summary

    A) There are minimal reports of overdose with this agent. No fatalities have been reported with reboxetine alone. One patient ingested 52 mg reboxetine and developed minimal toxicity; up to 240 mg have been ingested with survival reported.
    B) Overdose effects are anticipated to be an exaggeration of adverse clinical effects.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) ORAL - 8 to 10 milligrams/day in two divided doses; maximum daily dose 12 milligrams (Gutierrez et al, 1999).
    2) ELDERLY - 4 to 6 milligrams/day ( Gutierrez et al, 1999; Bergmann, 2000).
    3) REFRACTORY DEPRESSION - Anecdotal reports have suggested that combination therapy with reboxetine (doses of 8 to 12 milligrams/day) and a SSRI have been more effective in patients unresponsive to monotherapy with an SSRI (Fava, 2000).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) The safety and effectiveness in the pediatric population have not been established.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) At the time of this review, fatalities have NOT been reported with reboxetine only overdoses. One death was reported after an overdose of reboxetine and amitriptyline; dose amounts were unknown (Burns, 2000).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Individuals have survived ingestions of up to 240 milligrams (Burns, 2000).
    2) Of four known cases of overdose reported to the manufacturer, ECG abnormalities, coma or seizures did NOT occur with reboxetine only ingestions. Theoretically, seizures are possible following overdose with reboxetine (Burns, 2000).
    3) Overdose effects are anticipated to be an exaggeration of adverse clinical effects (Burns, 2000).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Reboxetine is structurally similar to fluoxetine, but it selectively and potently inhibits the reuptake of noradrenaline (Massana, 1998; Delgado & Michaels, 1999). It has no affinity for serotonin or dopamine reuptake sites and has negligible affinity for muscarinic, histaminic, or adrenergic receptors (Gutierrez et al, 1999). Reboxetine is a racemic mixture with two enantiomers, R,R(-) and S,S(+), with two chiral centers (Dostert et al, 1997).

Physicochemical

Molecular Weight

    A) 313.4 (M Sweetman , 2000).

References

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