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MIANSERIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Mianserin is a tetracyclic piperazino-azepine second-generation antidepressant. Mianserin is a dibenzobicyclo-octadiene similar to maprotiline.

Specific Substances

    1) 1,2,3,4,10,14b-Hexahydro-2-methyldibenzo
    2) (c,f)pyrazino(1,2-a)azepine
    3) 2-methyl-1,2,3,4,10,14b-hexahydro-2H-pyrazino
    4) (1,2-f)morphanthridine
    5) Molecular Formula: C18-H2-0-N2.HCL
    6) CAS 24219-97-4 (mianserin)
    7) CAS 21535-47-7 (mianserin hydrochloride)

Available Forms Sources

    A) FORMS
    1) Mianserin was first synthesized in 1966 and has been marketed in Europe since 1976 by Organaon International.
    2) Mianserin is available in Europe as 10 mg, 20 mg, and 30 mg tablets.
    B) USES
    1) Mianserin is indicated for the treatment of depression (S Sweetman , 2002).

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) Therapeutic dose adverse effects include drowsiness, blood dyscrasias, arthralgia, edema, and akathisias.
    B) WITH POISONING/EXPOSURE
    1) Toxic ingestion has resulted in bradycardia, tachycardia, hypotension, hypertension, conduction disturbances including complete heart block, seizures, delirium, and coma.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hypertension, hypotension, and tachycardia have occurred in overdose.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Anticholinergic signs of mydriasis and xerostomia, common to tricyclic antidepressant agents, may NOT occur with mianserin.
    2) Ototoxicity has been reported.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Bradycardia, hypotension, and ventricular tachycardia (very rare) have developed with therapeutic doses.
    B) WITH POISONING/EXPOSURE
    1) Conduction disturbances including complete heart block and ventricular fibrillation have occurred in several cases of mianserin intoxication.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Seizures, coma, and drowsiness have occurred.
    B) WITH THERAPEUTIC USE
    1) Seizures, delirium, hyperkinesia, and dyskinesia have occurred.
    2) Of the antidepressants, the incidence of seizures with mianserin is second only to that of maprotiline. Several cases of restless legs syndrome have also been reported.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Anticholinergic effects including delayed gastric emptying and quiet or absent bowel sounds, common to tricyclic agents, may NOT occur with mianserin. Salivation may increase.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Several cases of hepatic injury, ranging from elevated liver enzymes to cholestatic jaundice, have been reported.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Therapeutic use of mianserin has been associated with the development of agranulocytosis and granulocytopenia.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Skin rash and facial edema have occurred with therapeutic use. Erythema multiforme has also been reported.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Arthralgia and arthritis may occur with therapeutic use.
    0.2.19) IMMUNOLOGIC
    A) WITH THERAPEUTIC USE
    1) Severe allergic responses to mianserin have occurred with therapeutic use.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the teratogenic potential of this agent. In addition, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Laboratory Monitoring

    A) Monitor CBC, urinalysis, and liver and kidney function tests in patients with significant exposure.
    B) Although not commonly available, mianserin and N-desmethylmianserin levels may be clinically useful in determining severity.
    C) Institute continuous cardiac monitoring in all patients.
    D) Monitor blood pressure, pulse, respiratory rate, and pulse oximetry.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for seizures.
    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) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    D) VENTRICULAR DYSRHYTHMIAS/SUMMARY: Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    F) HYPERTENSION: Monitor vital signs regularly. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Sedation with benzodiazepines may be helpful in agitated patients with hypertension and tachycardia. For severe hypertension sodium nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. See main treatment section for doses.
    G) Cardiac conduction defects have been reported and cardiac monitoring is recommended.
    H) Physostigmine may INDUCE SEIZURES in the mianserin-poisoned patient and should NOT be used.

Range Of Toxicity

    A) The minimum lethal human dose to this agent has not been delineated. One patient survived an ingestion of 900 mg mianserin hydrochloride, despite development of complete heart block. Another patient developed hypotension and bradycardia after ingesting 300 mg of mianserin. She recovered following supportive care.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Therapeutic dose adverse effects include drowsiness, blood dyscrasias, arthralgia, edema, and akathisias.
    B) WITH POISONING/EXPOSURE
    1) Toxic ingestion has resulted in bradycardia, tachycardia, hypotension, hypertension, conduction disturbances including complete heart block, seizures, delirium, and coma.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypertension, hypotension, and tachycardia have occurred in overdose.
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Hypotension was reported following one 30 mg dose in an adult (Gallerani et al, 1996).
    B) WITH POISONING/EXPOSURE
    1) Hypertension and hypotension have occurred.
    a) CASE SERIES - Of 19 adults who had overdosed with mianserin, hypertension occurred in 3 patients, and hypotension occurred in 1 patient (Crome & Newman, 1977).
    3.3.5) PULSE
    A) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 50-year-old female with no history of cardiac abnormalities experienced an acute, symptomatic episode of sinus bradycardia following a single therapeutic dose of mianserin. Atropine restored normal heart rate. Readministration of mianserin resulted in a recurrence of bradycardia (Carcone et al, 1991).
    b) CASE REPORT - Bradycardia was reported following a therapeutic dose in an adult (Gallerani et al, 1996).
    B) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia occurred in 2 of 19 adults who had overdosed with mianserin (Crome & Newman, 1977).

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Anticholinergic signs of mydriasis and xerostomia, common to tricyclic antidepressant agents, may NOT occur with mianserin.
    2) Ototoxicity has been reported.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Mydriasis, normally seen with tricyclic antidepressants, may NOT occur with mianserin (Wilson et al, 1980).
    3.4.4) EARS
    A) TINNITUS
    1) WITH THERAPEUTIC USE
    a) Tinnitus has been reported as a side effect of mianserin at therapeutic doses of mianserin.
    B) OTOTOXICITY
    1) WITH THERAPEUTIC USE
    a) OTOTOXICITY has been reported.
    b) CASE REPORT - Permanent hearing loss occurred in a 27-year-old male following 2 years of therapeutic mianserin usage. Immediately after starting mianserin, he complained of bilateral tinnitus for 3 years. He discontinued use of mianserin after 2 years, but continued to experience tinnitus. Audiometry revealed a bilateral, symmetrical high frequency sensorineural hearing loss (Marais, 1991).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Bradycardia, hypotension, and ventricular tachycardia (very rare) have developed with therapeutic doses.
    B) WITH POISONING/EXPOSURE
    1) Conduction disturbances including complete heart block and ventricular fibrillation have occurred in several cases of mianserin intoxication.
    3.5.2) CLINICAL EFFECTS
    A) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Mianserin shortened QS2I and LVETI (left ventricular ejection time index), possibly through its effects on the peripheral vasculature rather than direct action on the heart (Burgess et al, 1980).
    B) VENTRICULAR FIBRILLATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 61-year-old male with a history of myocardial infarction and depression developed ventricular fibrillation 6 hours after ingesting a large, unspecified quantity of mianserin. Electrical defibrillation restored sinus rhythm. Intravenous lidocaine was administered. Polymorphous ventricular tachycardia without QTc prolongation and ventricular fibrillation recurred 28 hours later. Defibrillation was repeated and antiarrhythmic therapy was changed to procainamide. The patient recovered without further episodes (Haefeli & Schoenenberger, 1991).
    C) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 50-year-old female experienced an acute episode of symptomatic sinus bradycardia following a single therapeutic dose of mianserin. Heart rate was restored by atropine injection. Bradycardia recurred following readministration of mianserin (Carcone et al, 1991).
    b) CASE REPORT - A 35-year-old man developed bradycardia and hypotension following one 30 milligram dose of mianserin. His pulse was 41 beats/minute and blood pressure 50/30 mmHg ten minutes after receiving the drug. Hypotension and bradycardia resolved after 13 hours of treatment with intravenous fluids (Gallerani et al, 1996).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 37-year-old woman developed hypotension and bradycardia (40 to 50 beats/min) approximately 6 hours after ingesting 30 tablets of mianserin 10 mg. Following supportive care, her blood pressure and pulse rate normalized (Koseoglu et al, 2010).
    D) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 35-year-old man developed bradycardia and hypotension following one 30 milligram dose of mianserin. His pulse was 41 beats/minute and blood pressure 50/30 mmHg ten minutes after receiving the drug. Hypotension and bradycardia resolved after 13 hours of treatment with intravenous fluids (Gallerani et al, 1996).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 37-year-old woman developed hypotension (BP 70/40 mm Hg) and bradycardia approximately 6 hours after ingesting 30 tablets of mianserin 10 mg. Following supportive care, her blood pressure and pulse rate normalized (Koseoglu et al, 2010).
    E) HEART BLOCK
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 62-year-old female developed complete heart block approximately 4 hours after ingestion of 900 mg of mianserin hydrochloride. Cardiopulmonary resuscitation was performed and sinus rhythm returned within 5 minutes without pharmacological intervention. Heart block recurred at 5 and 1/2 hours after ingestion, reverting to sinus bradycardia within 1 minute of resuscitation. Pulse and blood pressure returned to normal following injection of 0.6 mg atropine. A temporary pacing device was introduced and the patient recovered without further episodes (Hla & Boyd, 1987).
    b) CASE REPORT - A 39-year-old female ingested 580 mg mianserin, 35 mg diazepam, and 30 mg nitrazepam. ECG showed first-degree heart block, which spontaneously reverted to sinus rhythm 16 hours after ingestion (Green & Kendall-Taylor, 1977).
    F) VENTRICULAR TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Ventricular tachycardia was reported with therapeutic use of mianserin (Haine et al, 2006).
    b) CASE REPORT - A 43-year-old woman developed palpitations a few months after starting mianserin 15 mg/day for sleep disturbance. Her medical history was unremarkable with no prior coronary risk factors. Frequent ventricular premature beats, which could be felt by the patient, were noted on physical exam and ECG. Holter monitoring revealed more than 10,000 monomorphic ventricular premature beats (VPB) per 24 hours (>10% of total beats), with couplets, triplets and runs of ventricular tachycardia up to a maximum of 39 consecutive beats. The heart was structurally normal on exam by MRI. Two weeks after discontinuation of mianserin, the ECG changes resolved and Holter monitoring reveled a single VPB in 24 hours (Haine et al, 2006).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Seizures, coma, and drowsiness have occurred.
    B) WITH THERAPEUTIC USE
    1) Seizures, delirium, hyperkinesia, and dyskinesia have occurred.
    2) Of the antidepressants, the incidence of seizures with mianserin is second only to that of maprotiline. Several cases of restless legs syndrome have also been reported.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported with mianserin therapeutic use. Predisposing factors include past history of seizures, a new or changed dose of mianserin, benzodiazepine withdrawal, and concomitant use of other epileptogenic drugs (Edwards & Glen-Bott, 1983). Of the antidepressants, the frequency of seizures with mianserin is second only to that of maprotiline (Edwards, 1979).
    b) EEG changes during seizures of two patients taking mianserin included slow activity with periodic complexes similar to those of Creutzfelt-Jakob disease (Koponen et al, 1990).
    c) CASE REPORT - A 43-year-old male taking 100 mg phenytoin 3 times a day for epilepsy had 3 generalized tonic-clonic seizures 13 days after beginning mianserin therapy for depression. He had been seizure-free for 1 year prior to this episode. He was treated with 300 mg phenytoin orally, mianserin was discontinued, and he resumed his previous phenytoin dosage the following day. No further seizures occurred (Evans & Lander, 1980).
    d) CASE REPORT - A 60-year-old female with no history of epilepsy had a grand-mal seizure 6 weeks after starting mianserin. Lorazepam had been discontinued 3 days before the seizure. Mianserin was discontinued and there have been no further seizures (Tyrer et al, 1979).
    2) WITH POISONING/EXPOSURE
    a) Seizures have been reported with mianserin overdose. Predisposing factors include past history of seizures, a new or changed dose of mianserin, benzodiazepine withdrawal, and concomitant use of other epileptogenic drugs (Edwards & Glen-Bott, 1983).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) Coma occurred in 2 of 19 adults following mianserin overdose (Crome & Newman, 1977).
    C) DELIRIUM
    1) WITH THERAPEUTIC USE
    a) Patients have developed delirium following seizures during mianserin therapy (Koponen et al, 1990).
    D) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Drowsiness occurred in 13 of 19 adults following mianserin overdose (Crome & Newman, 1977).
    E) HYPERACTIVE BEHAVIOR
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 44-year-old female complained of difficulty falling asleep and poorly localized, non-throbbing aches in lower legs following 10 days of mianserin 90 mg/day. Diazepam 10 mg/day did not relieve her symptoms. She reported frequent rubbing of her legs and the need to walk around to relieve the discomfort, which began in the evening and continued through the night. Neurological exam was unremarkable and serum levels were within the normal range. Mianserin was discontinued for 3 days and the symptoms disappeared. Reintroduction of mianserin 90 mg/day over four days resulted in reappearance of the unpleasant sensation. Mianserin was discontinued and replaced with amitriptyline 100 mg/day. The symptom did not reoccur (Piak et al, 1989).
    b) CASE REPORT - A 49-year-old female reported a disturbing sensation in her legs on day 10 of mianserin 60 mg/day therapy. The sensation occurred primarily in the evening causing her to move her legs; relief was obtained by vigorous rubbing of the legs. Neurologic exam and serum levels were within normal parameters. Replacement of mianserin with amitriptyline resulted in disappearance of the symptom within three days (Piak et al, 1989).
    c) CASE REPORT - A 45-year-old female complained of an unpleasant sensation in her legs relieved by moving or rubbing the legs following 2 weeks of mianserin 90 mg/day therapy. Neurologic exam was unremarkable. Decreasing the dose of mianserin to 60 mg/day did not result in improvement. Decreasing the dose to 30 mg/day relieved the symptom (Piak et al, 1989).
    F) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 30-year-old developmentally disabled (IQ 30) developed lip-puckering and chewing movements during the second week of mianserin therapy. In addition she demonstrated torticollis turning to the right side and deviations of her eyes and lips to the right. Mianserin therapy was continued despite the oral dyskinesia. Eight weeks later mianserin was discontinued and the involuntary movements resolved (Otani et al, 1989a).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Anticholinergic effects including delayed gastric emptying and quiet or absent bowel sounds, common to tricyclic agents, may NOT occur with mianserin. Salivation may increase.
    3.8.2) CLINICAL EFFECTS
    A) EXCESSIVE SALIVATION
    1) WITH THERAPEUTIC USE
    a) CASE SERIES - Four of 5 patients in a study exhibited increased salivation at 1 and 2 hours following a single 60 mg dose of mianserin (Wilson et al, 1980).
    B) GLOSSITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 77-year-old woman developed extensive facial edema, protrusion of the eyes, and prolapse and inflammation of the conjunctiva, after two days of mianserin 30 mg/day. Her tongue and buccal mucosa were swollen, resulting in obstruction of the oropharynx and dysphagia. These effects disappeared within 4 days of discontinuation of mianserin (Leibovitch et al, 1989).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Several cases of hepatic injury, ranging from elevated liver enzymes to cholestatic jaundice, have been reported.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 46-year-old male developed cholestatic jaundice after 14 days of mianserin 30 mg daily. Liver enzymes returned to normal within 6 weeks of discontinuing mianserin (Otani et al, 1989).
    b) CASE REPORT - A 48-year-old female developed asymptomatic liver injury in day 28 of therapeutic mianserin. Liver enzymes returned to normal 3 weeks after discontinuing mianserin (Otani et al, 1989).
    c) CASE REPORT - A 63-year-old female took mianserin 30 mg daily for 5 days, then 50 mg daily. On day 12, liver enzymes indicated hepatic injury. Mianserin dose was reduced to 30 mg daily, then reduced again on day 19 to 20 mg daily. Liver enzymes were normal by day 26 (Otani et al, 1989).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Therapeutic use of mianserin has been associated with the development of agranulocytosis and granulocytopenia.
    3.13.2) CLINICAL EFFECTS
    A) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Mianserin has been associated with agranulocytosis more commonly than any other antidepressant. A direct toxic effect on the bone marrow has been suggested. Epidemiologic studies indicate that blood dyscrasias typically develop in the elderly and after 4 to 6 weeks of therapy within normal dosage range (Chaplin, 1986).
    b) The frequency with which mianserin was associated with agranulocytosis in New Zealand was 1 in 1354 to 1743 (Coulter & Edwards, 1990).
    c) CASE REPORT - A 75-year-old male developed agranulocytosis 5 weeks after starting mianserin 10 mg 4 times a day. His CBC showed a white cell count of 3.4 x 10(9)/L with 0 neutrophils, lymphocytes 66%, monocytes 34%, and a platelet count of 212 x 10(9)/L. Bone marrow examination showed hypoplasia affecting myeloid series. His bone marrow function and CBC returned to normal within 2 weeks of mianserin discontinuation (Achar, 1982).
    d) CASE REPORT - A 70-year-old female, given mianserin and venlafaxine consecutively, developed agranulocytosis (a granulocyte level of 58/microliter and a total WBC count of 2,900/microliter) approximately 3 weeks after discontinuing mianserin therapy and 5 days after beginning venlafaxine therapy. The patient completely recovered following discontinuation of venlafaxine treatment; however, the exact causal agent of the agranulocytosis was not established (Lucht et al, 2000).
    e) CASE REPORT - An 85-year-old woman, on prednisone 10 mg/day for 7 months for arthritis and an unknown dose of amiodarone for one year for a dysrhythmia, developed agranulocytosis 12 weeks after starting mianserin 60 mg/day. A bone marrow biopsy confirmed a lack of white blood cell precursors. Her bone marrow function and CBC returned to normal levels 8 days after discontinuing her mianserin therapy. She remained on her prednisone and amiodarone and had a repeat CBC within normal limits at 6 months follow-up (Launay et al, 2000).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Skin rash and facial edema have occurred with therapeutic use. Erythema multiforme has also been reported.
    3.14.2) CLINICAL EFFECTS
    A) MACULOPAPULAR ERUPTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 39-year-old female with a history of acute psychotic episodes developed a pruriginous maculopapular rash over her limbs and trunk within 7 days of 90 mg/day of mianserin. The eruption continued and within 5 days the patient developed a massive facial edema, mild hepatocellular injury and prominent eosinophilia. Mianserin was discontinued and the rash resolved with prednisone therapy. Rechallenge with mianserin resulted in severe pruritus and a macular exanthema over the limbs and trunk (Bazin et al, 1991).
    B) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 20-year-old female developed erythema multiforme after taking mianserin for 5 weeks. The rash resolved with oral prednisone and discontinuation of mianserin. Lesions reappeared 2 days after reintroduction of mianserin, despite prednisone 20 mg/day (Cox, 1983).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Arthralgia and arthritis may occur with therapeutic use.
    3.15.2) CLINICAL EFFECTS
    A) ARTHRITIS
    1) WITH THERAPEUTIC USE
    a) Mianserin is frequently associated with the development of joint symptoms and arthritis (Ostensen & Myhr, 1991).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia has been reported in 4 patients, 2 with diet controlled diabetes and 2 non-diabetic, taking therapeutic doses of mianserin (Marley & Rohan, 1993).

Immunologic

    3.19.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Severe allergic responses to mianserin have occurred with therapeutic use.
    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 20-year-old female developed erythema multiforme after taking mianserin for 5 weeks. The rash resolved with oral prednisone and discontinuation of mianserin. Lesions reappeared 2 days after reintroduction of mianserin, despite prednisone 20 mg/day (Cox, 1983).
    b) CASE REPORT - A 77-year-old woman developed extensive facial edema, protrusion of the eyes, and prolapse and inflammation of the conjunctive, after two days of mianserin 30 mg/day. Her tongue and buccal mucosa were swollen, resulting in obstruction of the oropharynx and dysphagia. These effects disappeared within 4 days of discontinuation of mianserin (Leibovitch et al, 1989).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the teratogenic potential of this agent. In addition, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) 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 or lactation.

Carcinogenicity

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

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC, urinalysis, and liver and kidney function tests in patients with significant exposure.
    B) Although not commonly available, mianserin and N-desmethylmianserin levels may be clinically useful in determining severity.
    C) Institute continuous cardiac monitoring in all patients.
    D) Monitor blood pressure, pulse, respiratory rate, and pulse oximetry.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor CBC, urinalysis, and liver and kidney function tests in patients with significant exposure.
    2) Although not commonly available, mianserin and N-desmethylmianserin plasma levels may be helpful in determining the extent of toxicity.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Institute continuing cardiac monitoring in all patients.
    b) Monitor pulse, blood pressure, respiratory rate, and pulse oximetry.

Methods

    A) CHROMATOGRAPHY
    1) High-performance liquid chromatography has been used to determine mianserin in plasma (Brown et al, 1992).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

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

Monitoring

    A) Monitor CBC, urinalysis, and liver and kidney function tests in patients with significant exposure.
    B) Although not commonly available, mianserin and N-desmethylmianserin levels may be clinically useful in determining severity.
    C) Institute continuous cardiac monitoring in all patients.
    D) Monitor blood pressure, pulse, respiratory rate, and pulse oximetry.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for seizures.
    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) SUMMARY
    1) A toxic dose has not been established. Measures to prevent absorption following large oral doses may include gastric lavage and/or activated charcoal/cathartic. Emesis is not recommended because of the potential for seizures.
    B) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for seizures.
    C) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. Seizures may occur and should be treated aggressively. Cardiac conduction defects have been reported and cardiac monitoring is recommended.
    2) Physostigmine may INDUCE SEIZURES in the mianserin-poisoned patient and should not be used.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    C) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    4) PROCAINAMIDE
    a) PROCAINAMIDE/INDICATIONS
    1) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010; Vanden Hoek,TL,et al).
    b) PROCAINAMIDE/ADULT LOADING DOSE
    1) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010).
    2) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010).
    3) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010).
    c) PROCAINAMIDE/CONTROLLED INFUSION
    1) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)
    d) PROCAINAMIDE/ADULT MAINTENANCE DOSE
    1) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010).
    e) PROCAINAMIDE/PEDIATRIC LOADING DOSE
    1) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).
    f) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE
    1) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    g) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE
    1) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    h) MONITORING PARAMETERS
    1) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).
    i) AVOID
    1) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010).
    D) 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).
    E) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    F) BRADYCARDIA
    1) ATROPINE
    a) ATROPINE/DOSE
    1) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    2) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    a) There is no minimum dose (de Caen et al, 2015).
    b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    2) ISOPROTERENOL
    a) ISOPROTERENOL INDICATIONS
    1) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
    2) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
    3) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    4) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

Enhanced Elimination

    A) SUMMARY
    1) Because mianserin is 90% bound to plasma protein and its volume of distribution exceeds 3000 liters, it is unlikely that hemodialysis or peritoneal dialysis would be effective in enhancing elimination.
    B) HEMODIALYSIS
    1) In one study involving overdosage of mianserin, hemodialysis was ineffective in clearing the drug from serum (Jansen et al, 1977).

Abstracts

Case Reports

    A) ADULT
    1) A 62-year-old female ingested 900 mg of mianserin. Two and one-half hours after ingestion she was drowsy, with a pulse of 78 and blood pressure 210/110 mmHg. Four hours after ingestion she collapsed; cardiopulmonary resuscitation restored sinus rhythm without pharmacological intervention. She regained consciousness and her blood pressure returned to normal.
    a) Five and one-half hours post ingestion she collapsed, again requiring resuscitation. The monitor showed complete heart block, which reverted to sinus bradycardia (40 beats per minute) within 1 minute. Pulse and blood pressure returned to normal following injection of 0.6 mg atropine. A temporary pacing device was introduced and the patient recovered without further episodes (Hla & Boyd, 1987).
    2) A 53-year-old female took 600 mg mianserin with sleeping pills (10 grams of a carbromal-like monoureides) and 250 mL of 40% ethanol. She was found unconscious three hours after the ingestion and presented to the ED in a deep coma. Systolic blood pressure was 80 mmHg. Heart rate ranged from 100 to 110. Repeated electrocardiograms showed no abnormalities except for left axis deviation.
    a) Hemodialysis was performed for 6 hours. The patient awoke 17 hours after the ingestion and the remainder of her hospitalization was uneventful. Pharmacokinetic analysis of her mianserin plasma levels showed first-order kinetics not affected by hemodialysis.
    b) The half-life of the elimination phase was similar to that for therapeutic doses. Peak level was 780 mcg/L at 5 hours; therapeutic levels range from 30 to 120 mg/L (Jansen et al, 1977).

Range Of Toxicity

Summary

    A) The minimum lethal human dose to this agent has not been delineated. One patient survived an ingestion of 900 mg mianserin hydrochloride, despite development of complete heart block. Another patient developed hypotension and bradycardia after ingesting 300 mg of mianserin. She recovered following supportive care.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) ORAL -
    a) Doses utilized in clinical trials have been 30 to 60 milligrams orally daily, in divided doses. Doses of 120 milligrams daily (Jaskari et al, 1979) and 160 milligrams daily (Hodel & Trum, 1977) have been utilized.
    b) Initial dosage recommendations are 30 milligrams daily in hospitalized inpatients and in ambulatory patients, with dosage being adjusted based upon clinical response. Most patients respond to doses of 40 to 80 milligrams daily. The dose may also be administered as a single dose at bedtime (Brogden et al, 1978).

Minimum Lethal Exposure

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

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) One patient survived an ingestion of 900 milligrams mianserin hydrochloride, despite development of complete heart block (Hla & Boyd, 1987).
    2) CASE REPORT: A 37-year-old woman developed hypotension and bradycardia approximately 6 hours after ingesting 30 tablets of mianserin 10 mg. Following supportive care, her blood pressure and pulse rate normalized (Koseoglu et al, 2010).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) There are conflicting data in the literature with regard to therapeutic plasma mianserin levels. One study reported improvement with steady-state mianserin levels ranging from 28 to 72 micrograms per liter (Perry et al, 1978).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Serum concentrations following ingestion of 58 10-milligram tablets were as follows -
    HOURS AFTER INGESTIONSERUM MIANSERIN HCL (mcg/L)
    3.5439
    9157
    2186
    2770

    b) Side effects and toxicity of mianserin were not correlated with plasma levels in one study (Coppen et al, 1978).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 130 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 365 mg/kg (RTECS , 2001)
    3) LD50- (ORAL)RAT:
    a) 925 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Mianserin is a central serotonin antagonist with few anticholinergic effects. It does not affect the reuptake of amines, but enhances norepinephrine release through inhibition of the alpha-2 adrenoreceptors. Mianserin does not inhibit monoamine oxidase activity.

Toxicologic Mechanism

    A) Riley et al (1988) proposed a mechanism of toxicity in which one or more cytotoxic metabolites are produced by hepatic microsomes.

Physicochemical

Physical Characteristics

    A) Mianserin hydrochloride is a white or almost white crystalline powder or crystals (S Sweetman , 2002).

Ph

    A) A 1% solution of mianserin hydrochloride in water has a pH of 4.0 to 5.5 (S Sweetman , 2002).

Molecular Weight

    A) 300.8 (S Sweetman , 2002)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Achar KN: Mianserin-induced agranulocytosis. BMJ 1982; 285:208.
    3) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    4) Bazin N, Beaufils B, & Feline A: A severe allergic reaction to mianserin. Am J Psychiatry 1991; 128:1088.
    5) Bouhouch R, El Houari T, Fellat I, et al: Pharmacological therapy in children with nodal reentry tachycardia: when, how and how long to treat the affected patients. Curr Pharm Des 2008; 14(8):766-769.
    6) Brogden RN, Heel RC, & Speight TM: Mianserin: a review of its pharmacological properties and therapeutic efficacy in depressive illness. Drugs 1978; 16:273-301.
    7) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    8) Brown LW, Hdundt KL, & Swart KJ: Automated high-performance liquid chromatography method for the determination of mianserin in plasma using electrochemical detection. J Chromatogr 1992; 582:268-272.
    9) Burgess CD, Montgomery SA, & Montgomery DB: Cardiovascular effects of amitriptyline, mianserin and zimelidinein depressed patients. Prog Neuro-psychopharmacol 1980; 4:523-526.
    10) Carcone B, Vial T, & Chiallet N: Symptomatic bradycardia caused by mianserin at therapeutic doses. Hum Exp Toxicol 1991; 10:383-384.
    11) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    12) Chaplin S: Bone marrow depression due to mianserin, phenylbutazone, oxyphenbutazone, and chloramphenicol, part I. Adverse Drug React Acute Poison Rev 1986; 2:97-136.
    13) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    14) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    15) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    16) Coppen A, Ghose K, & Swade C: Effect of mianserin hydrochloride on peripheral uptake mechanisms for noradrenaline and 5-hydroxytryptamine in man. Br J Clin Pharmacol 1978; 5(Suppl 1):13S-17S.
    17) Coulter DM & Edwards IR: Mianserin and agranulocytosis in New Zealand. Lancet 1990; 336:785-787.
    18) Cox NH: Erythema multiforme due to mianserin - a case against generic prescribing. B J Clin Prac 1983; 39:293-294.
    19) Crome P & Newman B: Poisoning with maprotiline and mianserin (letter). BMJ 1977; 2:260.
    20) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    21) DeRidder JJ, Koppens PC, & van Hal HJ: Mass fragmentographic assay of nanogram amounts of the antidepressant drug mianserin hydrochloride (Org GB 94) in human plasma. J Chromatogr 1977; 143:289-297.
    22) Edwards JG & Glen-Bott M: Mianserin and convulsive seizures. Br J Clin Pharmacol 1983; 15:299S-311S.
    23) Edwards JG: Antidepressants and convulsions (letter). Lancet 1979; 2:1368-1369.
    24) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    25) Evans L & Lander CM: Mianserin and epilepsy (letter). Med J Aust 1980; 2:462-463.
    26) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    27) Gallerani M, Ricci L, & Calo G: Bradycardia and hypotension after the first administration of a therapeutic dose of mianserin. A case report. Clin Drug Invest 1996; 12:53-56.
    28) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    29) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    30) Green SDR & Kendall-Taylor P: Heart block in mianserin hydrochloride overdose. BMJ 1977; 2:1190.
    31) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    32) Haefeli WE & Schoenenberger RA: Recurrent ventricular fibrillation in mianserin intoxication. BMJ 1991; 302:415-416.
    33) Haine SE, Miljoen HP, Blankoff I, et al: Mianserin and ventricular tachycardia: case report and review of the literature. Cardiology 2006; 106(4):195-198.
    34) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    35) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    36) Hla KK & Boyd O: Mianserin and complete heart block. Human Toxicol 1987; 6:401-402.
    37) Hodel J & Trum JM: Results of a field trial with a new anti-depressive compound in ambulatory and hospitalized patients. Schweiz Rundsch Med Prax 1977; 66:1085-1092.
    38) Hrdina PD, Lapierre YD, & McIntosh B: Mianserin kinetics in depressed patients. Clin Pharmacol Ther 1983; 33:757-762.
    39) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    40) Jansen FW, Drykoningen G, & DeRidder JJ: Poisoning with antidepressants (letter). Br Med J 1977; 2:896.
    41) Jansen H: Workshop on the clinical pharmacology and efficacy of mianserin: pharmacokinetics. Proceedings of a symposium on mianserin. Br J Clin Pharmacol 1978; 5:96S.
    42) Jaskari MO, Ahlfors UG, & Ginman L: Treatment of depression. Comparative study on the effects of mianserin (Tolvin) and amitriptyline. Ther Gegen 1979; 118:806-818.
    43) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    44) Koponen H, Honkonen S, & Partanen J: Epileptic attack, delerium, and periodic complexes in the EEG during mianserin treatment. Neuropsychobiology 1990; 23:164-168.
    45) Koseoglu Z , Kara B , & Satar S : Bradycardia and hypotension in mianserin intoxication. Hum Exp Toxicol 2010; 29(10):887-888.
    46) Lambert C, Park BK, & Kitteringham NR: Activation of mianserin and its metabolites by human liver microsomes. Biochem Pharmacol 1989; 38:2853-2858.
    47) Launay D, Queyrel V, Hatron PY, et al: [Agranulocytosis connected with the taking of mianserin: a complication to be feared in the aged]. Rev Med Interne 2000; 21(7):642-643.
    48) Leibovitch G, Maaravi Y, & Shalev O: Severe facial oedema and glossitis associated with mianserin (letter). Lancet 1989; 2:871-872.
    49) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    50) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    51) Lucht MJ, Kleinschmidt R, & Maier W: Agranulocytosis during treatment with mianserin and venlafaxine (letter). J Clin Psychopharmacol 2000; 20:490-491.
    52) Luedtke SA, Kuhn RJ, & McCaffrey FM: Pharmacologic management of supraventricular tachycardias in children. Part 2: Atrial flutter, atrial fibrillation, and junctional and atrial ectopic tachycardia. Ann Pharmacother 1997; 31(11):1347-1359.
    53) Mandapati R , Byrum CJ , Kavey RE , et al: Procainamide for rate control of postsurgical junctional tachycardia. Pediatr Cardiol 2000; 21(2):123-128.
    54) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    55) Marais J: Cochleotoxicity due to mianserin hydrochloride. J Laryngol & Otol 1991; 105:475-476.
    56) Marley J & Rohan A: Mianserin-induced hyperglycemia (letter). Lancet 1993; 342:1430-1431.
    57) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    58) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    59) Ostensen M & Myhr K: Mianserin as a cause of arthritis (letter). Br J Rheumatol 1991; 30:74-75.
    60) Otani K, Kaneko S, & Fukushima Y: Involuntary movements associated with mianserin treatment. B J Psychol 1989a; 154:113-114.
    61) Otani K, Kaneko S, & Tasaki H: Hepatic injury caused by mianserin. BMJ 1989; 299:519.
    62) Palha AP, Ferreira L, & Abreu-Lima C: A double-blind trial comparing mianserin and maprotiline in depressed inpatients. Clin Ther 1985; 7:584-592.
    63) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    64) Perry GF, Fitzsimmons B, & Shapiro L: Clinical study of mianserin, imipramine and placebo in depression: blood level and MHPG correlations. Br J Clin Pharmacol 1978; 5(Suppl 1):35-41.
    65) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    66) Product Information: Cordarone(R) oral tablets, amiodarone HCl oral tablets. Wyeth Pharmaceuticals Inc (per FDA), Philadelphia, PA, 2015.
    67) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    68) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    69) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    70) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    71) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    72) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    73) Product Information: procainamide HCl IV, IM injection solution, procainamide HCl IV, IM injection solution. Hospira, Inc (per DailyMed), Lake Forest, IL, 2011.
    74) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires July/31/2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    75) Ratnasamy C, Rossique-Gonzalez M, & Young ML: Pharmacological therapy in children with atrioventricular reentry: which drug?. Curr Pharm Des 2008; 14(8):753-761.
    76) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    77) Roberts P, Kitteringham NR, & Park BK: Species differences in the activation of mianserin to a cytotoxic metabolite. Drug Metabolism and Disposition 1991; 19:841-843.
    78) S Sweetman : Martindale: The Complete Drug Reference. Pharmaceutical Press. London, England (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    79) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    80) Seppala T: Psychomotor skills during acute and two-week treatment with mianserin (ORG GB 94) and amitriptyline, and their combined effects with alcohol. Ann Clin Res 1977; 9:66-72.
    81) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    82) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    83) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    84) Tyrer P, Steinberg B, & Watson B: Possible epileptogenic effect of mianserin. Lancet 1979; 2:798-799.
    85) Vanden Hoek TL, Morrison LJ, Shuster M, et al: Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S829-S861.
    86) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    87) Walsh EP , Saul JP , Sholler GF , et al: Evaluation of a staged treatment protocol for rapid automatic junctional tachycardia after operation for congenital heart disease. J Am Coll Cardiol 1997; 29(5):1046-1053.
    88) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.