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MIRTAZAPINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Mirtazapine is a tetracyclic antidepressant belonging to the piperazinoazepine group of compounds. It is a 5-HT2 and 5-HT3 receptor antagonist, a histamine-1 receptor antagonist, a moderate peripheral alpha-1 adrenergic antagonist, and a moderate muscarinic receptor antagonist. It is a noradrenergic and specific serotonergic antidepressant (NaSSA).

Specific Substances

    1) 1,2,3,4,10,14B-hexahydro-2-methylpyrazino(2,1-A) pyrido (2,3-C) benzazepine
    2) 6-Azamianserin
    3) Mepirzepine
    4) ORG 3770
    5) CAS 61337-67-5

Available Forms Sources

    A) FORMS
    1) Mirtazapine is available as 7.5 mg, 15 mg, 30 mg, and 45 mg oral tablets and 15 mg, 30 mg, and 45 mg orally disintegrating tablets (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011; Prod Info mirtazapine oral tablets, 2005).
    B) USES
    1) Mirtazapine is used to treat major depressive disorders (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011).

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: Mirtazapine is used to treat major depressive disorders.
    B) PHARMACOLOGY: Mirtazapine is a tetracyclic antidepressant belonging to the piperazinoazepine group of compounds. Evidence indicates that mirtazapine may enhance central noradrenergic and serotonergic activity, possibly through its antagonist activity at central presynaptic alpha2-adrenergic inhibitory autoreceptors and heteroreceptors. It is a potent 5-HT2 and 5-HT3 receptor antagonist, a histamine (H1) receptor antagonist, a moderate peripheral alpha-1 adrenergic antagonist, and a moderate muscarinic receptor antagonist.
    C) TOXICOLOGY: Mirtazapine produces sedative effects due to potent histamine (H1) receptor antagonism, orthostatic hypotension due to moderate alpha-1 adrenergic receptor antagonism, and relatively low incidence of anticholinergic side effects due to a moderate muscarinic receptor antagonism.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Somnolence, dizziness, constipation. OTHER EFFECTS: Dry mouth, dizziness, disorientation, impaired memory, nausea, vomiting, orthostatic hypotension, hyponatremia, arthralgia, and myalgia. RARE: Severe skin reactions (eg, bullous dermatitis, erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis), elevated liver enzymes, pancreatitis, agranulocytosis, pancytopenia, anemia, thrombocytopenia, leukopenia, lymphocytosis, lymphadenopathy, seizures, and restless leg syndrome. Potentially life-threatening serotonin syndrome and neuroleptic malignant syndrome have been reported in patients receiving mirtazapine therapy. The risk is increased with concomitant use of SSRIs, serotonin norepinephrine reuptake inhibitors (SNRI), triptans, and MAOIs (contraindicated).
    F) WITH POISONING/EXPOSURE
    1) Overdose of mirtazapine alone with no co-ingestants is associated with only mild clinical symptoms. Reported overdose effects have included drowsiness, disorientation, tremor, headache, impaired memory, tachycardia, bradycardia, hypotension, hypertension, nausea, vomiting, ataxia, miosis, blurred vision, hepatitis, and rhabdomyolysis.
    0.2.20) REPRODUCTIVE
    A) Mirtazapine is classified as FDA pregnancy category C. A case report and animal studies have shown no evidence of teratogenicity from mirtazapine. Administer mirtazapine during pregnancy only when clearly needed. Use caution administering mirtazapine to nursing women as mirtazapine may be excreted in human breast milk.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential with platelet count, serum electrolytes, and liver enzymes in symptomatic patients.
    D) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    E) Monitor for clinical evidence of neuroleptic malignant syndrome and serotonin syndrome following an overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Treat mild hyponatremia with water restriction and/or 0.9% sodium chloride.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV fluids, dopamine, or norepinephrine. Manage severe hyponatremia with 0.9% sodium chloride; 3% sodium chloride may be necessary in patients with severe hyponatremia. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Although rare, treat neuroleptic malignant syndrome with oral bromocriptine, IV benzodiazepines in conjunction with cooling and other supportive measures. Consider dantrolene in severe cases.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is alert and able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression or seizures.
    E) ANTIDOTE
    1) None.
    F) HYPONATREMIA
    1) Evaluate for hyponatremia and associated symptoms. Patients with mild symptoms can be managed with water restriction. Patients with moderate to severe symptoms should receive 0.9% sodium chloride (rarely 3% NaCl in patients with very severe symptoms). The goal is slow correction; the serum sodium should not increase more than 2 mEq/L/hour in any 4-hour period or more than 15 mEq/L per day. Rapid correction may cause central pontine myelinolysis. Monitor serum electrolytes, fluid intake and output, and urine volume and electrolytes.
    G) SEIZURES
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    H) NEUROLEPTIC MALIGNANT SYNDROME
    1) Oral bromocriptine, IV benzodiazepines in conjunction with cooling and other supportive measures. Consider dantrolene in severe cases.
    I) SEROTONIN SYNDROME
    1) Primary treatment is sedation with IV benzodiazepines, and cooling measures. CYPROHEPTADINE: A serotonin antagonist with high affinity for the 5-HT2 receptors; effective for milder cases of serotonin syndrome. Dose: ADULT: 12 mg orally or nasogastric tube, followed by 4 to 8 mg every 4 to 6 hours. CHILD: 0.25 mg/kg/day orally or nasogastric tube divided every 6 hours, maximum dose 12 mg/day. CHLORPROMAZINE: A phenothiazine antipsychotic with 5-HT2 antagonist activity; indicated in severe serotonin syndrome cases. Dose: 12.5 to 50 mg IV, followed by 25 to 50 mg every 6 hours. It is NOT generally recommended because it may cause severe hypotension. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with nondepolarizing agents.
    J) RHABDOMYOLYSIS
    1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.
    K) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding of mirtazapine.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with severe neutropenia should be admitted to the hospital.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    M) PITFALLS
    1) When managing a suspected mirtazapine overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    N) PHARMACOKINETICS
    1) Absorption: rapid and complete. Absolute oral bioavailability: about 50%. Tmax: approximately 2 hours. Protein binding: approximately 85%. Metabolism: extensively metabolized; major pathways of biotransformation include demethylation and hydroxylation followed by glucuronide conjugation. Renal excretion: primarily eliminated via the urine (75%). Elimination half-life: approximately 20 to 40 hours.
    O) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers), myelosuppression; sedating agents (eg, ethanol, benzodiazepine/barbiturate, antipsychotics); other antidepressants.

Range Of Toxicity

    A) TOXICITY: Severe toxicity is unlikely from mirtazapine alone. Adults have ingested up to 4.5 grams and recovered with supportive care. An accidental overdose of 60 mg in a 3-year-old child resulted in tachycardia. The child was alert, responsive, and interactive and recovered with no adverse sequelae. A 34-month-old girl developed somnolence, nausea, and vomiting after ingesting 165 mg of mirtazapine (15 mg/kg).
    B) THERAPEUTIC: ADULT: 15 mg/day as a single dose orally; may increase in dose every 1 to 2 weeks to a maximum dose of 45 mg/day. PEDIATRIC: Safety and efficacy in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Mirtazapine is used to treat major depressive disorders.
    B) PHARMACOLOGY: Mirtazapine is a tetracyclic antidepressant belonging to the piperazinoazepine group of compounds. Evidence indicates that mirtazapine may enhance central noradrenergic and serotonergic activity, possibly through its antagonist activity at central presynaptic alpha2-adrenergic inhibitory autoreceptors and heteroreceptors. It is a potent 5-HT2 and 5-HT3 receptor antagonist, a histamine (H1) receptor antagonist, a moderate peripheral alpha-1 adrenergic antagonist, and a moderate muscarinic receptor antagonist.
    C) TOXICOLOGY: Mirtazapine produces sedative effects due to potent histamine (H1) receptor antagonism, orthostatic hypotension due to moderate alpha-1 adrenergic receptor antagonism, and relatively low incidence of anticholinergic side effects due to a moderate muscarinic receptor antagonism.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Somnolence, dizziness, constipation. OTHER EFFECTS: Dry mouth, dizziness, disorientation, impaired memory, nausea, vomiting, orthostatic hypotension, hyponatremia, arthralgia, and myalgia. RARE: Severe skin reactions (eg, bullous dermatitis, erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis), elevated liver enzymes, pancreatitis, agranulocytosis, pancytopenia, anemia, thrombocytopenia, leukopenia, lymphocytosis, lymphadenopathy, seizures, and restless leg syndrome. Potentially life-threatening serotonin syndrome and neuroleptic malignant syndrome have been reported in patients receiving mirtazapine therapy. The risk is increased with concomitant use of SSRIs, serotonin norepinephrine reuptake inhibitors (SNRI), triptans, and MAOIs (contraindicated).
    F) WITH POISONING/EXPOSURE
    1) Overdose of mirtazapine alone with no co-ingestants is associated with only mild clinical symptoms. Reported overdose effects have included drowsiness, disorientation, tremor, headache, impaired memory, tachycardia, bradycardia, hypotension, hypertension, nausea, vomiting, ataxia, miosis, blurred vision, hepatitis, and rhabdomyolysis.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MIOSIS: Miosis has been reported following overdose with mirtazapine in 2 women. The doses reported were 240 mg and 1680 mg, respectively (Langford et al, 2003).
    2) BLURRED VISION: A 40-year-old man experienced blurred vision after taking 1.8 g of mirtazapine and 2 L of wine (Kuliwaba, 2005).
    3) VISUAL ABNORMALITY: A 34-month-old girl (weight: 11 kg) developed somnolence, nausea, vomiting, and a visual abnormality in spatial comprehension of objects about 3 hours after ingesting 5.5 mirtazapine tablets (total dose: 165 mg; 15 mg/kg) (Akbayram et al, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia was reported following overdose, either with mirtazapine alone or in combination with other drugs, during premarketing clinical studies. ECG changes were not observed following the overdose, however, approximately 3% of patients in clinical studies were reported to have ECG changes that were reportedly not significant (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011).
    b) CASE SERIES: In a retrospective review of overdose cases (n=23; average age 27 years [range 6 to 82 years]) involving mirtazapine (mean ingestion of 343 mg; range, 15 to 1500 mg), tachycardia (111 to 135 bpm) was reported in 3 patients (LoVecchio et al, 2008).
    c) CASE REPORT: Accidental overdose of 60 mg in a 3-year-old child produced tachycardia (139 beats/minute). No other adverse effects were reported, and the child recovered with no adverse sequelae (Bremner et al, 1998).
    d) CASE REPORT: A 40-year-old man with a past history of cognitive impairment secondary to carbon monoxide poisoning and depression developed tachycardia (pulse 108) after taking 1.8 g of mirtazapine and 2 L of wine. Following supportive therapy, he recovered without further sequelae (Kuliwaba, 2005).
    e) CASE SERIES: In a retrospective review of overdose cases involving mirtazapine (n = 117), approximately 30% (n = 35) of the cases presented with tachycardia with a median heart rate of 87 beats per minute (range: 54-140 beats per minute) (Waring et al, 2007).
    f) CASE SERIES: In an observational case series of 267 mirtazapine overdoses, 89 single-agent mirtazapine ingestions (median dose ingested: 420 mg; interquartile range [IQR]: 270 to 750 mg; range: 150 to 1350 mg) with or without ethanol were identified. Tachycardia (maximum heart rate of greater than 99 beats/min; median maximum HR: 92 beats/min; IQR: 81 to 101 beats/min; range: 50 to 175 beats/min) was observed in 29 patients (33%) (Berling & Isbister, 2014).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Clinically significant orthostatic hypotension was reported in normal subjects given mirtazapine in early pharmacology studies and infrequently observed in premarketing trials when given to depressed patients (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011; Prod Info mirtazapine oral tablets, 2005).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Following an overdose of mirtazapine 1200 mg and lorazepam 20 mg and laying outside for 10 hours at a temperature of 0 degrees C, a 41-year-old woman was transferred to the ED with a blood pressure of 90/60 mm Hg. Her body temperature was reduced to 26 degrees C. Recovery was complete (Retz et al, 1998).
    b) CASE SERIES: In a retrospective review of overdose cases (n=23; average age 27 years [range 6 to 82 years]) involving mirtazapine (mean ingestion of 343 mg; range, 15 to 1500 mg), hypotension (91/56 mm Hg) was reported in one patient (LoVecchio et al, 2008).
    c) CASE SERIES: In an observational case series of 267 mirtazapine overdoses, 89 single-agent mirtazapine ingestions (median dose ingested: 420 mg; interquartile range [IQR]: 270 to 750 mg; range: 150 to 1350 mg) with or without ethanol were identified. The minimum blood pressure of less than 90 mmHg (median maximum systolic BP: 112 mmHg; IQR: 101 to 127 mmHg; range: 86 to 161 mmHg) developed in 2 patients (2%), with systolic BPs of 86 mmHg (Berling & Isbister, 2014).
    C) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In an observational case series of 267 mirtazapine overdoses, 89 single-agent mirtazapine ingestions (median dose ingested: 420 mg; interquartile range [IQR]: 270 to 750 mg; range: 150 to 1350 mg) with or without ethanol were identified. The maximum blood pressure of greater than 140 mmHg (median maximum systolic BP: 130 mmHg; IQR: 122 to 147 mmHg; range: 100 to 215 mmHg) developed in 32 patients (36%) (Berling & Isbister, 2014).
    D) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) One study reported a patient with bradydysrhythmia and atrial fibrillation with a heart rate of 42 bpm on ECG following an overdose of mirtazapine 1200 mg and lorazepam 20 mg complicated by severe environmental hypothermia (core temperature 26 C). Complete right bundle branch block and a prolonged QT interval (660 ms, QTc 552 ms) was also apparent on ECG readings. Following rewarming and supportive care, the dysrhythmias resolved and the patient was discharged on day 5. The dysrhythmias were most likely secondary to the hypothermia (Retz et al, 1998).
    E) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) A case of bilateral peripheral edema after one month of therapy with mirtazapine (45 mg/day) was reported in a 60-year-old male. Other concomitant medications the patient had been taking for over 6 months included aspirin, atenolol, gabapentin, naproxen and lorazepam. Following the discontinuation of mirtazapine, the peripheral edema improved. Re-challenge was not attempted (Kutscher et al, 2001).
    F) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective review of overdose cases (n=23; average age 27 years [range 6 to 82 years]) involving mirtazapine (mean ingestion of 343 mg; range, 15 to 1500 mg), bradycardia (51 bpm) was reported in one patient (LoVecchio et al, 2008).
    b) CASE SERIES: In an observational case series of 267 mirtazapine overdoses, 89 single-agent mirtazapine ingestions (median dose ingested: 420 mg; interquartile range [IQR]: 270 to 750 mg; range: 150 to 1350 mg) with or without ethanol were identified. The minimum heart rate of less than 61 beats/min (median minimum HR: 75 beats/min; IQR: 66 to 86 beats/min; range: 50 to 139 beats/min) developed in 9 patients (10%) (Berling & Isbister, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Somnolence is the most common adverse effect of mirtazapine (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011; Claghorn et al, 1987; Mattila et al, 1989; Fink & Irwin, 1982; Claghorn & Lesem, 1995; Bremner, 1995). Other common effects include dizziness, disorientation, and impaired memory.
    b) INCIDENCE: In a premarketing clinical trial, up to 54% of patients experienced somnolence and 7% experienced dizziness (Prod Info Remeron(R), mirtazapine, 2001; Mattila et al, 1989).
    c) In premarketing clinical studies, tremor, confusion, abnormal thinking, and abnormal dreams were reported in 1% or more of the patients, and were more frequent than in the placebo group (Prod Info Remeron(R), mirtazapine, 2001).
    d) Similar degrees of somnolence were reported with amitriptyline in two studies, with an incidence greater than 60% (Mattila et al, 1989; Smith et al, 1990).
    e) Decreased alertness, drowsiness, weakness and difficulty with vision occurred following single doses of mirtazapine in depressed patients in a dose-ranging, crossover clinical trial (Fink & Irwin, 1982).
    2) WITH POISONING/EXPOSURE
    a) Drowsiness, disorientation, and impaired memory have been reported after overdose (Waring et al, 2007; Raja & Azzoni, 2002; Schaper et al, 2002; Velazquez et al, 2001; Prod Info mirtazapine oral tablets, 2005; Bremner et al, 1998; Holzbach et al, 1998; Gerritsen, 1997). Following an overdose of 900 mg, an 81-year-old woman was admitted in a semi-comatose condition, with no other reported neurological symptoms. Following arousal, she was observed with transitory somnolence for 3 days (Hoes & Zeijpveld, 1996). A 63-year-old woman was admitted to the hospital with only moderate sedation following an overdose of greater than 900 mg (Raja & Azzoni, 2002).
    b) CASE REPORT: A 34-month-old girl (weight: 11 kg) developed somnolence, nausea, and vomiting about 3 hours after ingesting 5.5 mirtazapine tablets (total dose: 165 mg; 15 mg/kg) (Akbayram et al, 2012).
    c) CASE SERIES: In a retrospective review of overdose cases (n=23; average age 27 years [range 6 to 82 years]) involving mirtazapine (mean ingestion of 343 mg; range, 15 to 1500 mg), drowsiness and agitation were reported in 8 and 1 patients, respectively (LoVecchio et al, 2008).
    d) CASE REPORT: A 43-year-old woman with depression and posttraumatic stress disorder developed vomiting, somnolence and ataxia after ingesting 4.5 g of mirtazapine in a suicide attempt. EEG showed slow alpha-waves, but was judged as normal. Following supportive therapy, she recovered completely without further sequelae (Garlipp et al, 2003).
    e) CASE SERIES: Four patients (n=6) experienced CNS depressant effects following overdoses of 10 to 30 times the maximum recommended doses. These effects may be attributable to co-ingestion of other depressant medications. All patients fully recovered (Bremner et al, 1998).
    f) CASE REPORT: A 40-year-old man experienced dizziness, tremor, and headache after ingesting 1.8 g of mirtazapine, and 2 L of wine (Kuliwaba, 2005).
    g) CASE SERIES: In a retrospective review of overdose cases involving mirtazapine (n = 117), approximately 27% of the cases presented with drowsiness and reduced level of consciousness. In patients who ingested mirtazapine alone with no co-ingestants, symptoms resolved without intervention (Waring et al, 2007).
    h) CASE SERIES: In an observational case series of 267 mirtazapine overdoses, 89 single-agent mirtazapine ingestions (median dose ingested: 420 mg; interquartile range [IQR]: 270 to 750 mg; range: 150 to 1350 mg) with or without ethanol were identified. The minimum Glasgow Coma score (GCS) of less than 15 developed in 41 patients (46%) at least once during their admission. All patients had a GCS between 9 to 14 (Berling & Isbister, 2014).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizure has only been reported in one patient out of 2,796 in premarketing clinical trials, and in none of the 8 overdose cases reported in premarketing clinical trials (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011).
    b) CASE REPORT: A 48-year-old woman with psychotic disorder experienced status epilepticus within 2 days following dose increase of mirtazapine and antipsychotic medication switch from quetiapine to olanzapine. A brain MRI 10 days prior revealed no pathological findings, and the patient had no prior history of seizures or head trauma. Laboratory tests at hospital admission for psychogenic vomiting and anorexia showed no biochemical or hematological disturbances. The patient was prescribed quetiapine 600 mg which was abruptly discontinued due to the lack of efficacy and suspicion of the patient not receiving the drug (expectorated tablets found). Therefore, the patient was switched to orally-dispersible olanzapine 10 mg, and the dose was quickly titrated to 30 mg. Mirtazapine 30 mg was also initiated 4 days prior to the seizure and then increased to 60 mg 2 days prior to the incident. On day 16 of hospitalization, the patient developed generalized tonic-clonic seizure which progressed to status epilepticus. CT tomography revealed no abnormalities, and neurological examination showed no focal neurological signs. Olanzapine and mirtazapine were discontinued and IV phenytoin was initiated. Phenytoin was discontinued 1 month later without complications and the patient remained seizure-free (Spyridi et al, 2009).
    2) WITH POISONING/EXPOSURE
    a) Seizure has only been reported in one patient out of 2,796 in premarketing clinical trials, and in none of the 8 overdose cases reported in premarketing clinical trials (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011).
    C) AKATHISIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 38-year-old man presented with sleeplessness and rapid weight loss during the previous 2 months, as well as sadness, hopelessness, guilt, and exhaustion. There was no personal or family history of akathisia, psychiatric illness, or drug abuse. Following a diagnosis of depressive disorder, mirtazapine 30 mg/day was initiated. Within 4 hours of the initial dose the patient experienced severe motor restlessness and an inability to sit still, which emerged during wakefulness. Treatment included diazepam 5 mg IV which resolved the akathisia symptoms within 30 minutes. Mirtazapine was discontinued and citalopram was instituted, which resulted in 12 weeks of stability with no further akathisia episodes (Gulsun & Doruk, 2008).
    b) CASE REPORT: A 52-year-old man developed akathisia within an hour of taking mirtazapine 30 mg for depression. His symptoms of restlessness and inability to keep his legs still were resolved within 30 minutes by clonazepam 1 mg. Akathisia symptoms recurred with the next day's dose and were again successfully treated with clonazepam. With continuing mirtazapine, his depression improved, and the akathisia gradually resolved with regular use of clonazepam. A 73-year-old woman with chronic depression developed akathisia with mirtazapine 30 mg. Her depression worsened when her treatment was switched to fluvoxamine. Mirtazapine was reintroduced and, at a dose of 30 mg, again caused akathisia. Reduction of the dose to 15 mg per night relieved the akathisia. No additional treatment was necessary (Girishchandra et al, 2002).
    D) DYSTONIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 63-year-old man developed upper-extremity dystonia 10 days after starting treatment with mirtazapine 15 mg per day for depression. The man was taking quinapril (to control hypertension) and insulin (for type 2 diabetes), neither of which was thought likely to interact with mirtazapine. He also snorted heroin and had done so 3 days before admission. Discontinuation of mirtazapine resulted in complete resolution of the dystonia within 4 days (Lu et al, 2002).
    E) ATAXIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 43-year-old woman with depression and posttraumatic stress disorder developed vomiting, somnolence and ataxia after ingesting 4.5 g of mirtazapine in a suicide attempt. Following supportive therapy, she recovered completely without further sequelae (Garlipp et al, 2003).
    F) RESTLESS LEGS
    1) WITH THERAPEUTIC USE
    a) In a prospective, naturalistic study of patients (median age, 46 years; range, 18 to 87 years) treated with antidepressants, 24 of 271 (9%) subjects experienced new-onset restless leg syndrome (RLS) or worsening of preexisting RLS as a side effect related to treatment. Antidepressants included fluoxetine, paroxetine, citalopram, sertraline, escitalopram, venlafaxine, duloxetine, reboxetine, and mirtazapine. Approximately 28% of patients receiving mirtazapine experienced newly occurred or deteriorating RLS. The other antidepressants showed RLS symptoms (newly occurred or deteriorated) at the rate of 5% to 10%; no cases occurred in patients taking reboxetine. Subjects stated symptoms occurred early in treatment (median of 2.5 days, range 1 to 23 days) (Rottach et al, 2008).
    b) CASE REPORT: A 56-year-old Korean woman developed restless leg syndrome (RLS) 4 days after beginning treatment with mirtazapine for depression. Mirtazapine 15 milligrams (mg) per day was started in the evening for depression, and alprazolam 0.5 mg/day in the morning for anxiety. On the fifth day, she experienced leg restlessness and "creepy-crawly" sensations and aching in both legs about 1 hour after taking mirtazapine. Clonazepam 0.5 mg/day was added to her regimen. She continued to have RLS. Mirtazapine was switched to paroxetine 20 mg/day, and 4 days later, RLS had disappeared (Bahk et al, 2002).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth has occurred in 25% to 54% of patients during premarketing clinical studies following therapeutic doses (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011; Bremner, 1995).
    b) Dry lips and mouth have been reported following single doses of mirtazapine (Fink & Irwin, 1982; Bremner et al, 1998).
    B) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Infrequently (1%), vomiting and/or diarrhea have been reported (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) Nausea has been reported following mirtazapine overdose (Kuliwaba, 2005).
    b) CASE REPORT: A 43-year-old woman with depression and posttraumatic stress disorder developed vomiting, somnolence and ataxia after ingesting 4.5 g of mirtazapine in a suicide attempt. Following supportive therapy, she recovered completely without further sequelae (Garlipp et al, 2003).
    c) CASE REPORT: A 34-month-old girl (weight: 11 kg) developed somnolence, nausea, and vomiting about 3 hours after ingesting 5.5 mirtazapine tablets (total dose: 165 mg; 15 mg/kg) (Akbayram et al, 2012).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation has developed in up to 13% of patients during premarketing clinical studies following therapeutic doses (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011; Bremner, 1995).
    b) A 13% incidence of constipation was reported by Smith et al (1990) in a double-blind comparative study.
    D) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: In a case report, a 40-year-old man with a history of alcohol consumption of 8 to 16 units per week experienced recurrent pancreatitis on 6 different occasions over a 3-year time period while receiving mirtazapine for depression. Other causative factors were ruled out including gallstones, alcohol, autoimmune disease, and steroids. There is no information reported on whether the mirtazapine was ever discontinued or if pancreatis ever reoccurred (Hussain & Burke, 2008).
    b) CASE REPORT: A case of subclinical pancreatitis related to mirtazapine therapy has been reported in a 54-year-old woman with a past history of alcohol abuse. On day 4 of mirtazapine therapy, elevated lipase and pancreas-specific amylase was noted on routine blood sampling. Following discontinuation of mirtazapine, lipase and amylase levels returned to normal (Sommer et al, 2001).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In premarketing evaluations of 2,796 patients given multiple doses of mirtazapine, elevated liver enzymes was reported on at least one occasion in at least 1 in 100 patients (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011; Prod Info REMERON(R) oral tablets, 2009).
    b) One study reported two patients that developed elevated serum hepatic enzyme levels with prolonged jaundice (3 months) following chronic mirtazapine therapy (1 to 3 years) (Hui et al, 2002).
    c) CASE REPORT: A 19-year-old man, with no history of substance abuse, negative test results for hepatitis A immunoglobulin M antibody, hepatitis C virus antibody, and hepatitis B virus surface antigen, and with normal baseline liver enzymes, experienced abdominal discomfort, nausea and vomiting, and elevated ALT (385 units/L) and AST (189 units/L) after 2 weeks of treatment with mirtazapine. His total bilirubin and alkaline phosphatase (ALP) levels stayed within normal limits. The patient had been initially started on mirtazapine 7.5 mg/day and had been increased to 30 mg/day after 8 days. He had also been taking lorazepam 0.5 mg/day and alprazolam 0.25 mg/day. Two weeks after the patient's medications were discontinued, his ALT and AST levels decreased to 30 units/L and 19 units/L, respectively (Kang et al, 2011).
    d) CASE REPORT: A 20-year-old African American man experienced asymptomatic increased liver enzyme levels within 3 months of beginning mirtazapine therapy (30 mg at night) for major depressive disorder. Prior to therapy initiation, a baseline diagnostic profile revealed normal electrolytes, urea, creatinine, lipid levels, and hepatic enzymes, and patient had no significant history of liver dysfunction, substance abuse, or other medical disorders. During treatment, patient denied the use of alcohol, illicit substances, or herbal supplements. Four weeks after a dose reduction to 15 mg per night, liver enzymes had decreased, but remained above the normal range. The patient chose to discontinue the mirtazapine, and liver enzyme levels returned to normal 2 months later. Patient refused mirtazapine rechallenge (Adetunji et al, 2007).
    B) INFLAMMATORY DISEASE OF LIVER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 40-year-old man with a past history of cognitive impairment secondary to carbon monoxide poisoning and depression developed rhabdomyolysis and hepatitis (albumin 45; alkaline phosphatase 81; bilirubin 4; GGT 102; AST 92; ALT 56; LD 502) after taking 1.8 g of mirtazapine and 2 L of wine. Following supportive therapy, he recovered without further sequelae. The authors suggested that concurrent use of mirtazapine and alcohol may have caused the hepatitis (Kuliwaba, 2005).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An 85-year-old man developed urinary retention within 24 hours of initiating treatment with mirtazapine 15 mg/day for depression. This patient had a history of asymptomatic age-related benign prostate hypertrophy and Parkinson's disease for which he was receiving treatment with a combination levodopa, carbidopa, and entacapone (200/50/800 mg/day, respectively). Within 24 hours of starting on mirtazapine, he developed acute urinary retention requiring catheterization. Mirtazapine was discontinued and within 24 hours, his urinary retention subsided. One week late, a rechallenge demonstrated the same pattern of urinary retention. The patient was switched to citalopram 20 mg/day without any urinary side effects. Over the course of the following year, his combination levodopa, carbidopa, and entacapone was increased (400/100/800 mg/day, respectively) without further urinary issues (Oulis et al, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) In premarketing clinical trials symptomatic agranulocytosis was reported in 2 out of 2796 patients and one patient developed severe neutropenia. All 3 patients recovered following discontinuation of mirtazapine (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011; Prod Info Remeron(R), mirtazapine, 2001). Although the incidence of agranulocytosis and neutropenia is low, the possibility exists following overdose.
    B) DISORDER OF HEMATOPOIETIC STRUCTURE
    1) WITH THERAPEUTIC USE
    a) Rarely reported adverse effects during premarketing clinical trials of mirtazapine have included pancytopenia, anemia, thrombocytopenia, leukopenia, lymphocytosis, lymphadenopathy, and petechiae (Prod Info Remeron(R), mirtazapine, 2001).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) Mirtazapine has been associated with cases of severe skin reactions, including bullous dermatitis, erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, during postmarketing surveillance (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011)

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Mirtazapine therapy has been associated with the development of joint symptoms, including arthralgias and myasthenia, during its use in premarketing clinical trials (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011). One patient developed some muscle rigidity for 45 minutes following a dose of mirtazapine, which subsided over the next several hours (Ruigt et al, 1990).
    B) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 40-year-old man with a past history of cognitive impairment secondary to carbon monoxide poisoning and depression developed rhabdomyolysis (CK 7578; 1% CK-MB; 24 hours later CK peak 9186; urine myoglobin 288 mcg; normal less than 150) after taking 1.8 g of mirtazapine and 2 L of wine. Following supportive therapy, he recovered without further sequelae (Kuliwaba, 2005).

Reproductive

    3.20.1) SUMMARY
    A) Mirtazapine is classified as FDA pregnancy category C. A case report and animal studies have shown no evidence of teratogenicity from mirtazapine. Administer mirtazapine during pregnancy only when clearly needed. Use caution administering mirtazapine to nursing women as mirtazapine may be excreted in human breast milk.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) A multicenter observational prospective cohort study compared the pregnancy outcomes of exposure to mirtazapine, exposure to any selective serotonin reuptake inhibitor, and no exposure. The rates of major birth defects did not differ significantly among the mirtazapine-exposed, SSRI-exposed, and control groups, and the overall pregnancy outcomes were comparable (Winterfeld et al, 2015).
    2) CASE REPORT: A 25-year-old woman delivered healthy twins after treatment with a German formulation of mirtazapine. During her first trimester, she was diagnosed with treatment-resistant hyperemesis gravidarum and secondary psychopathology. In her 15th week, intravenous mirtazapine 6 mg daily was given for 3 days, followed by oral mirtazapine 30 mg daily for 2 additional weeks. Mirtazapine was tapered over a 4-week period. At week 27 of gestation, nausea and vomiting occurred again and mirtazapine was given for another 6 weeks. She gave birth to two healthy infants at 36 weeks' gestation with no dysmorphology or laboratory abnormalities, and the neonatal course was uneventful. Infant exams were completely normal as determined by a pediatrician checkup at 6 months of age (Rohde et al, 2003).
    B) ANIMAL STUDIES
    1) RATS, RABBITS: Reproductive studies in rats and rabbits at doses of 20 and 17 times the maximum recommended human dose (MRHD), respectively, have shown no evidence of teratogenicity (Prod Info REMERON(R) oral tablets, 2011).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info REMERON(R) oral tablets, 2011).
    B) PREGNANCY CATEGORY
    1) Mirtazapine is classified as FDA pregnancy category C (Prod Info REMERON(R) oral tablets, 2011)
    2) Administer mirtazapine during pregnancy only when clearly needed (Prod Info REMERON(R) oral tablets, 2011).
    C) ANIMAL STUDIES
    1) RATS: Reproductive studies in rats have shown an increase in post-implantation losses in rat dams and a decrease in pup birth weights at mirtazapine doses 20 times the maximum recommended human dose (Prod Info REMERON(R) oral tablets, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Use caution administering mirtazapine to nursing women as mirtazapine may be excreted in human breast milk (Prod Info REMERON(R) oral tablets, 2011).
    2) Mirtazapine was excreted into the breast milk of a 35-year-old woman who was treated with mirtazapine from 4 weeks gestation throughout the rest of her pregnancy and during breastfeeding. The woman, who had 3 healthy sons, was initiated on mirtazapine 45 mg/day for depression. Mirtazapine was discontinued when she became pregnant. However, symptoms recurred 4 weeks into her pregnancy at which time mirtazapine 15 to 30 mg/day was reinitiated. Two months after delivering a healthy infant, the woman presented with concerns of a high birth and current weight and sedation because of differences in this infant compared with her others. Subsequently, breast milk levels and maternal serum were assessed in the morning 12 hours post-dose, and infant serum was obtained 2 hours postprandially. The maternal serum mirtazapine and breast milk content were 27 nanograms (ng)/mL and 15 ng/mL, respectively, with a serum to foremilk ratio of 0.55. The serum mirtazapine level in the infant was 10 ng/mL. Based on the mother's weight of 67 kg, she was receiving 224 mcg/kg/day suggesting that the infant's intake was 3 mcg/kg/day or 1.3%. Serum mirtazapine levels in relation to the weight-adjusted daily doses were 0.12 and 3.3 in the mother and infant, respectively, suggesting that the infant was 28 times less efficient than the mother in eliminating mirtazapine. Although there were high infant serum levels due to reduced elimination rates in the infant, authors indicate that an association between mirtazapine and increased weight and sedation in the infant cannot be made based on this case report alone (Tonn et al, 2009).
    B) LACK OF EFFECT
    1) A small, prospective study in breastfeeding women (n=8) receiving mirtazapine for perinatal and/or postnatal depression revealed modest transfer of mirtazapine into breast milk. The women (mean age 35 years) were receiving a single daily mirtazapine median dose of 38 mg (range, 30 to 120 mg) for a median duration of 32 days (range, 6 to 129 days) prior to the study. The infants (mean age, 6.3 months; range, 1.5 to 13 months) had a mean weight of 7.4 kg (range, 5.5 to 10.5 kg) at the start of the study. At steady state, milk samples (foremilk and hindmilk) were collected each time the infant was fed (3 to 4 hourly). For mirtazapine , the mean (n=8) maternal milk and plasma concentrations were 53 mcg/L (95% confidence interval (CI), 42 to 65) and 47 mcg/L (95% CI, 24 to 70), respectively. Mirtazapine concentrations were approximately 2-fold higher in the foremilk than the hindmilk (ratio, 2.3; 95% CI, 1.8 to 2.8). For desmethylmirtazapine (n=8), the mean maternal milk and plasma concentrations were 13 mcg/L (95% CI, 9 to 17) and 19 mcg/L (95% CI, 11 to 26), respectively. The mean (n=7) maternal milk to plasma ratio was 1.1 (95% CI, 0.7 to 1.5) for mirtazapine and 0.6 (95% CI, 0.5 to 0.7) for desmethylmirtazapine. The mean (n=8) relative infant doses for mirtazapine and desmethylmirtazapine were 1.5% (95% CI, 0.8 to 2.2) and 0.4% (95% CI, 0.2 to 0.6), respectively, of the weight-adjusted maternal dose. Mirtazapine was present in the plasma of only 1 infant (1.5 mcg/L); the desmethyl metabolite was not detected in any sample. However, this low concentration could be attributed to mirtazapine's extensive first-pass metabolism. No adverse events occurred in the infants (Kristensen et al, 2006).
    2) In a case report describing excretion of mirtazapine into the milk of a 35-year-old breastfeeding woman, mirtazapine was not detected in the infant's plasma. The woman (weight 60 kg) was receiving a nightly mirtazapine dose of 22.5 mg and had been exclusively breastfeeding her 6-week-old infant. Breast milk levels were assessed following 14 days of mirtazapine therapy and breast milk was collected (foremilk and hindmilk samples collected separately) at 4 and 10 hours post-dose. Maternal and infant plasma levels were assessed at 12.5 hour post-dose. The foremilk and hindmilk levels were significantly higher at 4 hours post-dose (130 nanograms (ng)/mL and 145 ng/mL, respectively) compared to 10 hours post-dose (61 ng/mL and 90 ng/mL, respectively). However, the weight-adjusted maternal dose was low, ranging from 3.9% to 4.4% at 4 hours and 1.8% to 2.7% at 10 hours post-dose. Mirtazapine was not detected in the infant's plasma at 12.5 hours post-dose. No abnormalities (sedation, weight gain) were evident in the infant at weekly follow-up visits (Klier et al, 2007).
    3) In a case report involving a 27-year-old woman with postpartum depression, mirtazapine was excreted into the milk of the nursing mother. The nursing infant was exposed to mirtazapine during maternal treatment of mirtazapine 30 mg/day at 9:00 p.m. Samples were taken after reaching steady state to determine concentrations of mirtazapine in breast milk and serum levels in the mother and infant. At 7:00 p.m. (22 hours post-dose), the maternal plasma level was 7 nanograms (ng)/mL with a concentration in the foremilk of 7 ng/mL and in the hindmilk of 18 ng/mL. A second sample taken at 12:00 a.m. (15 hours post-dose) found that the maternal plasma level was 25 ng/mL with a concentration in the foremilk of 28 ng/mL and in the hindmilk of 34 ng/mL. The infant's plasma concentration was 0.2 ng/mL. The infant's psychomotor development was examined by a neuropediatrician and no adverse effects could be detected. The infant did not experience sedation or abnormal weight gain from exposure to mirtazapine (Aichhorn et al, 2004).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) FEMALE RATS: When given mirtazapine doses that were 3 or more times the maximum recommended human dose (MRHD) on a mg/m(2) basis, rats showed disrupted estrous cycling. When rats were given mirtazapine doses that were 20 times the MRHD, preimplantation fetal losses occurred (Prod Info REMERON(R) oral tablets, 2011).
    2) RATS: Mating and conception in rats were not affected by mirtazapine at doses up to 20 times the MRHD (Prod Info REMERON(R) oral tablets, 2011).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) HEPATIC CARCINOMA
    1) An increased incidence of hepatocellular adenomas and carcinomas was reported in male mice receiving higher doses (200 mg/kg/day) of mirtazapine. Female rats receiving 20 to 60 mg/kg/day experienced a higher incidence of hepatocellular adenomas while male rats experienced a higher incidence of hepatocellular tumors and thyroid carcinomas at the higher doses (Prod Info Remeron(R), mirtazapine, 2001).

Genotoxicity

    A) Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage during in vitro tests in hamsters, rabbits and rats (Prod Info Remeron(R), mirtazapine, 2001).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential with platelet count, serum electrolytes, and liver enzymes in symptomatic patients.
    D) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    E) Monitor for clinical evidence of neuroleptic malignant syndrome and serotonin syndrome following an overdose.

Methods

    A) CHROMATOGRAPHY
    1) A capillary gas chromatographic assay method with nitrogen-sensitive detection for the determination of mirtazapine in human plasma is described in one study (Paanakker & van Hal, 1987).
    2) A gas chromatography-mass spectrometry method is described for the quantification of serum mirtazapine concentrations (Anttila et al, 2001).
    3) One study described a high-performance liquid chromatography with ultraviolet detection for the quantitation of mirtazapine and its demethyl metabolite in human plasma. The lower limit of quantification was 20 ng/mL for both mirtazapine and demethylmirtazapine. This RP-HPLC method utilized opipramol as the internal standard. This is a rapid method, with a run time <12 minutes. No interference from other psychotropic drugs was noted (Romiguieres et al, 2002).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with severe neutropenia should be admitted to the hospital.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential with platelet count, serum electrolytes, and liver enzymes in symptomatic patients.
    D) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    E) Monitor for clinical evidence of neuroleptic malignant syndrome and serotonin syndrome following an overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    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) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Monitor CBC with differential with platelet count, serum electrolytes, and liver enzymes in symptomatic patients.
    4) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    5) Monitor for clinical evidence of neuroleptic malignant syndrome and serotonin syndrome following an overdose.
    B) 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).
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) SEROTONIN SYNDROME
    1) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    2) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    3) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    4) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    5) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    6) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    7) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    8) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).
    E) NEUROLEPTIC MALIGNANT SYNDROME
    1) Neuroleptic malignant syndrome due to levodopa withdrawal may be successfully managed with diphenhydramine, oral bromocriptine, IV benzodiazepines, conjunction with cooling and other supportive care (May et al, 1983; Mueller et al, 1983; Leikin et al, 1987; Schneider, 1991; Barkin, 1992). Dantrolene may be considered in severe cases.
    2) BENZODIAZEPINES: In conjunction with cooling measures and supportive care, initial management of NMS should include administration of intravenous benzodiazepines for muscle relaxation (Goldfrank et al, 2002). Benzodiazepines may also be helpful in controlling agitation or reversal of catatonia (Caroff & Mann, 1993; Gratz et al, 1992).
    a) DIAZEPAM DOSE: 5 to 10 mg IV bolus to slow push initially, followed by 2.5 to 5 mg IV in 10 minutes. Titrate to achieve adequate sedation. Large doses may be needed.
    3) BROMOCRIPTINE DOSE: 5 mg 3 times a day orally (Mueller et al, 1983).
    4) DANTROLENE LOADING DOSE: 2.5 mg/kg, to a maximum of 10 mg/kg IV (Barkin, 1992).
    5) DANTROLENE MAINTENANCE DOSE: 2.5 mg/kg IV every 6 hours (Barkin, 1992); 1 mg/kg orally every 12 hours, up to 50 mg/dose has also been successful (May et al, 1983).
    a) EFFICACY: Variable; often ineffective as sole agent. Most efficacious in reducing rigidity and the fever that may be produced at a muscular level; will not always resolve mental status changes or psychotic symptoms that probably are more central in origin. Efficacy may be improved if given with a dopamine agonist (Granato et al, 1983; Blue et al, 1986; May et al, 1983).
    b) Some studies report NO beneficial effects and suggest that dantrolene might even worsen the course of NMS (Rosebush & Stewart, 1989).
    6) NON-PHARMACOLOGIC METHODS: Rapid cooling, hydration, and serial assessment of respiratory, cardiovascular, renal and neurologic function, and fluid status are used in conjunction with drug therapy and discontinuation of the antipsychotic agent (Knight & Roberts, 1986).
    7) In a review of 67 case reports of neuroleptic malignant syndrome, the onset of clinical response was shorter after treatment with dantrolene (mean 1.15 days) or bromocriptine (1.03 days) than with supportive measures alone (6.8 days). The time to complete resolution was also shorter with these therapeutic interventions (Rosenberg & Green, 1989).
    8) RETROSPECTIVE STUDY: A study comparing 438 untreated patients with neuroleptic malignant syndrome and 196 treated cases found that administration of dantrolene, bromocriptine, or amantadine significantly reduced the death rate in these cases. Death rate of untreated cases was 21%; administration of dantrolene alone (no dosage reported) decreased death rate to 8.6% (n=58); with bromocriptine alone death rate was 7.8% (n=51); and with amantadine alone death rate was 5.9% (n=17). In combination with other drugs, each of these drugs significantly decreased the NMS-related death rate, although the decrease was slightly less than for single administrations (Sakkas et al, 1991).
    9) RIGIDITY: Was slowly responsive to dantrolene 25 milligrams three times daily in a 76-year-old with NMS (Reutens et al, 1991).
    F) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding of mirtazapine.

Range Of Toxicity

Summary

    A) TOXICITY: Severe toxicity is unlikely from mirtazapine alone. Adults have ingested up to 4.5 grams and recovered with supportive care. An accidental overdose of 60 mg in a 3-year-old child resulted in tachycardia. The child was alert, responsive, and interactive and recovered with no adverse sequelae. A 34-month-old girl developed somnolence, nausea, and vomiting after ingesting 165 mg of mirtazapine (15 mg/kg).
    B) THERAPEUTIC: ADULT: 15 mg/day as a single dose orally; may increase in dose every 1 to 2 weeks to a maximum dose of 45 mg/day. PEDIATRIC: Safety and efficacy in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) 15 mg/day as a single dose orally; may increase in dose every 1 to 2 weeks to a max dose of 45 mg/day (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011).
    7.2.2) PEDIATRIC
    A) The safety and efficacy in pediatric patients have not been established (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) ADULT
    a) SUMMARY: An acute overdose of 30 to 45 mg of mirtazapine, in conjunction with overdoses of amitriptyline and chlorprothixene, produced tachycardia and central nervous depression, including disorientation, lethargy, and impaired memory (Prod Info REMERONSolTab(R) oral disintegrating tablets, 2011; Prod Info REMERON(R) oral tablets, 2011).
    1) Doses of up to 76 mg/day have been well tolerated in clinical studies (Bruijn et al, 1996).
    b) CASE SERIES/MINIMAL TOXICITY: In an observational case series of 267 mirtazapine overdoses, 89 single-agent mirtazapine ingestions (median dose ingested: 420 mg; interquartile range [IQR]: 270 to 750 mg; range: 150 to 1350 mg) with or without ethanol were identified and resulted in minimal toxicity following an overdose of mirtazapine alone. Adverse effects included tachycardia (heart rate greater than 99 beats/min; n=29; 33%), mild hypertension (BP greater than 140 mmHg; n=32; 36%), bradycardia (heart rate less than 61 beats/min; n=9; 10%), hypotension (BP less than 90 beats/min; n=2; 2%), and Glasgow Coma score (GCS) of less than 15 (range: 9 to 14; n=41; 46%). There were no reports of seizure, serotonin syndrome, an abnormal QT or need for respiratory support in patients that had ingested mirtazapine alone. In larger ingestions of mirtazapine (greater than 1000 mg), there was some reduction in Glasgow Coma Score but no intervention was necessary in any of these cases (Berling & Isbister, 2014).
    c) CASE SERIES: In a retrospective review of overdose cases (n=23; average age 27 years [range 6 to 82 years]) involving mirtazapine (mean ingestion of 343 mg; range, 15 to 1500 mg), drowsiness (n=8), agitation (n=1), tachycardia (n=3), hypotension (n=1) and bradycardia (n=1) were reported (LoVecchio et al, 2008).
    d) CASE SERIES: In a retrospective review of overdose cases involving mirtazapine (n = 117), mirtazapine overdose was associated with co-ingestion of alcohol in 59% (n = 69) of the cases, other medications in 59.8% (n = 70) of the cases, and both alcohol and other medications in 38.5% (n = 45) of the cases. The range of mirtazapine ingested was from 30 mg to 2520 mg. Mirtazapine alone in overdose was found to only cause mild clinical symptoms such as drowsiness and tachycardia. There was no evidence of significant clinical, laboratory, or ECG abnormalities in mirtazapine only ingestions. In those cases with more severe effects, toxicity could be attributed to the co-ingestants involved (Waring et al, 2007).
    e) CASE SERIES: In a series of 6 patients, with overdoses ranging from 10 to 30 times the maximum recommended dose (maximum dose, 1350 mg), all patients recovered with no serious adverse effects. No seizures were reported and no clinically significant changes in ECG or vital signs were seen. CNS depressant effects were seen in 4 patients, possibly due to concomitant ingestion of other CNS depressants (Bremner et al, 1998).
    f) CASE SERIES: In a series of 73 mono-intoxications with mirtazapine, no fatalities were reported. Dizziness, sleepiness, and gastrointestinal discomfort were reported. Results of the overdoses are as follows (Schaper et al, 2002):
    # OF CASESSEVERITYMAXIMUM DOSAGE
    31No symptoms900 mg
    32Minor2250 mg
    3Moderate900 mg
    1Severe600 mg
    6Incomplete documentationIncomplete documentation

    g) CASE REPORT: A 43-year-old woman developed vomiting, somnolence, and ataxia after ingesting 4.5 g of mirtazapine. EEG showed slow alpha-waves, but was judged as normal. Following supportive therapy, she recovered completely without further sequelae (Garlipp et al, 2003).
    h) CASE REPORT: A 34-year-old woman developed minor neurological deficits following an intentional ingestion of 1.68 g of mirtazapine and alcohol. No cardiac or respiratory effects were reported. Glasgow coma score was 8/15 on admission and miosis was reported. The patient had a complete neurological recovery within 14 hours with only supportive care (Langford et al, 2003).
    i) CASE REPORT: A 40-year-old man with a past history of cognitive impairment secondary to carbon monoxide poisoning and depression developed rhabdomyolysis, tachycardia, and hepatitis after taking 1.8 g of mirtazapine and 2 L of wine. The authors suggested that concurrent use of mirtazapine and alcohol may have caused the hepatitis. Following supportive therapy, he recovered without further sequelae (Kuliwaba, 2005).
    j) CASE REPORTS: Holzbach et al (1998) reported 2 patients who ingested 900 mg and 1500 mg, respectively, in suicide attempts. No complications developed and both patients made full and uneventful recoveries (Holzbach et al, 1998).
    k) CASE REPORT: The only adverse effects of an 810 mg mirtazapine and 300 mg dothiepin overdose were anxiety and confusion in a 45-year-old woman (Gerritsen, 1997).
    l) CASE REPORT: Following an overdose of mirtazapine 1200 mg and lorazepam 20 mg, complicated by severe environmental hypothermia (core temperature 26 C) a 41-year-old female was found with compromised cardiac and respiratory function. Following supportive therapy, she fully recovered by day 5 (Retz et al, 1998). Most of the observed effects were probably due to hypothermia.
    m) CASE REPORT: Following an overdose of 900 mg of mirtazapine and 210 mg of midazolam, an 81-year-old woman was admitted to the hospital in a semi-comatose state, with no other neurological signs/symptoms. After 1 hour the patient awoke spontaneously. Transitory somnolence was observed for 3 days (Hoes & Zeijpveld, 1996).
    n) CASE REPORT: A 63-year-old woman developed only moderate sedation following an overdose of greater than 900 mg of mirtazapine. No other drugs were taken in the overdose (Raja & Azzoni, 2002).
    o) CASE REPORT: Following an overdose of mirtazapine (375 mg) with ethanol, a 43-year-old male presented to the ED 2 hours later. Physical examination revealed a mild tachycardia (rate 112) and lethargy. ECG revealed sinus tachycardia, left ventricular hypertrophy, and non-specific ST-segment changes. The patient had a history of AIDS, atrial fibrillation, and alcohol abuse. Following decontamination with activated charcoal, the patient was observed overnight and discharged the next day (Velazquez et al, 2001).
    2) PEDIATRIC
    a) CASE REPORT: A 34-month-old girl (weight: 11 kg) developed somnolence, nausea, and vomiting after ingesting 165 mg of mirtazapine (15 mg/kg) (Akbayram et al, 2012).
    b) CASE REPORT: An accidental overdose of 60 mg in a 3-year-old child resulted in a rapid heart rate. Otherwise, the child was alert, responsive, and interactive. The child recovered with no adverse sequelae (Bremner et al, 1998).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Therapeutic serum levels have not been well established, however, one study based dosing of mirtazapine in their clinical trials on predefined mean serum levels of approximately 70 ng/mL, which were derived from steady-state blood levels of patients maintained on 60 mg/day in previous studies (Bruijn et al, 1996).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ADULT
    a) One study reported plasma levels of 2300 nanograms/mL approximately 18 hours after an overdose of 900 mg mirtazapine in a 44-year-old woman. Plasma level at 26 hours post-ingestion was 1370 nanograms/mL, which further decreased to 1060 ng/mL at 40 hours post-ingestion. No clinical complications were seen in conjunction with the high plasma levels (Holzbach et al, 1998).
    b) Plasma level of 368 ng/mL was reported 41 hours following an overdose of mirtazapine 1200 mg and lorazepam 20 mg in a 41-year-old woman (Retz et al, 1998).
    c) Serum mirtazapine level approximately two hours following a 375 mg overdose was 530 ng/mL in a 43-year-old man (Velazquez et al, 2001).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) ANTIHISTAMINIC/ANTISEROTONERGIC/NORADRENERGIC -
    1) SUMMARY: Mirtazapine acts as a potent and selective presynaptic alpha-2-adrenoceptor antagonist and enhances noradrenergic transmission by increasing noradrenergic cell firing and norepinephrine release.
    a) Mirtazapine is the 6-aza analogue of the tetracyclic antidepressant mianserin (Fink & Irwin, 1982; de Boer et al, 1988). Antihistaminic (H1) and antiserotonergic properties have been demonstrated (de Boer et al, 1988; Ruigt et al, 1990). Mirtazapine mainly affects serotonin (5-HT) receptors of the 5-HT2, 5-HTd, and 5-HT3 subtypes, possessing low affinity for 5-HT1A, 5-HT1B, and 5-HT1C receptors (Ruigt et al, 1990). As a 5-HT2 antagonist, mirtazapine is significantly less potent than mianserin (de Boer et al, 1988).
    b) The increase in extracellular 5-HT is most likely due to indirect alpha-1- adrenoceptor-mediated enhancement of 5-HT firing and direct blockade of inhibitory alpha-2-heteroreceptors located on 5-HT terminals (de Boer et al, 1994; de Boer et al, 1996).
    c) Mirtazapine blocks noradrenergic transmission by selectively blocking pre- and postsynaptic alpha-2-adrenoceptors (de Boer et al, 1988; de Boer et al, 1996).
    d) Similar to mianserin, mirtazapine has strong alpha-2 receptor blocking actions, but unlike mianserin, it has NO significant effect on the synaptic reuptake of catecholamines (Nickolson et al, 1982; de Boer et al, 1988; Ruigt et al, 1990; de Boer et al, 1994). Mirtazapine has actions similar to mianserin in healthy subjects (Fink & Irwin, 1982) and appears to be an effective antidepressant (Smith et al, 1990). Significant anxiolytic effects have been observed in animal studies, actions shared by mianserin (Sorensen et al, 1985).
    B) ENANTIOMERS
    1) Enantiomers of mirtazapine were shown to be stereoselective for alpha-2 antagonism in preclinical studies, with the most activity attributed to the (+)-enantiomer (Nickolson et al, 1982; Fink & Irwin, 1982). However, Fink & Irwin (1982) studied the effects on the central nervous system in healthy volunteers, and it appears that both (-)- and (+)-enantiomer possess antidepressant activity (Fink & Irwin, 1982).
    2) Enantiomers of mirtazapine appear to have no 5-HT3 agonist properties when studied in mouse neuroblastoma N1E-115 cells (Kooyman et al, 1994).
    C) ELECTROENCEPHALOGRAPHIC STUDIES: Pharmacologic and electroencephalographic (EEG) studies in healthy subjects have shown the effects of mirtazapine 2 mg to be similar to mianserin 6 mg. Mirtazapine was associated with slightly faster onset of action on the EEG and a tendency toward fewer anticholinergic effects than mianserin (Fink & Irwin, 1982).

Physicochemical

Physical Characteristics

    A) Mirtazapine is a slightly water soluble, white to creamy white crystalline powder (Prod Info Remeron(R), mirtazapine, 2001).

Molecular Weight

    A) 265.36

References

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