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LURASIDONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Lurasidone is a benzoisothiazol derivative, an atypical antipsychotic agent, that acts as an antagonist at dopamine type-2 (D2) and 5-hydroxytryptamine (5-HT)2A receptors.

Specific Substances

    1) SM-13496
    2) SMP-13496
    3) Lurasidone hydrochloride
    4) CAS 367514-87-2 (lurasidone)
    5) CAS 367514-88-3 (lurasidone hydrochloride)
    1.2.1) MOLECULAR FORMULA
    1) C28H36N402S.HCl (Prod Info LATUDA(R) oral tablets, 2010)

Available Forms Sources

    A) FORMS
    1) Lurasidone is available as 20 mg, 40 mg, 60 mg, 80 mg, and 120 mg tablets (Prod Info LATUDA(TM) oral tablets, 2013).
    B) USES
    1) Lurasidone an atypical antipsychotic indicated for the treatment of schizophrenia in adults. It is also indicated as either monotherapy or adjunctive therapy with lithium or valproate for the treatment of depressive episodes associated with bipolar I disorder in adults (Prod Info LATUDA(TM) oral tablets, 2013).

Overview

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Lurasidone plasma concentrations are not readily available or clinically useful in the treatment of overdose.
    C) Obtain a baseline ECG and repeat as needed; continuous cardiac monitoring may be necessary in symptomatic patients.
    D) Routine laboratory studies are not likely to be necessary.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Management will primarily be symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treat hypotension with IV fluids and pressors if needed (norepinephrine is preferred). Manage dystonic reactions with anticholinergic agents. Treat severe neutropenia with colony stimulating factors. Although rare, treat neuroleptic malignant syndrome with benzodiazepines, bromocriptine, consider dantrolene, as well as cooling and supportive measures.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal is not recommended due to the potential for somnolence or dystonic reactions and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal in a patient with a recent, substantial overdose who is alert or in whom airway is protected.
    D) AIRWAY MANAGEMENT
    1) Insure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression.
    E) ANTIDOTE
    1) None
    F) HYPOTENSIVE EPISODE
    1) Treat hypotension with intravenous fluids; add vasopressors if unresponsive to fluids. Norepinephrine is preferred; the manufacturer recommends avoidance of epinephrine and dopamine since beta stimulation may worsen hypotension in the setting of lurasidone-induced alpha blockade.
    G) NEUTROPENIA
    1) For severe neutropenia, administer colony stimulating factor. Filgrastim 5 mcg/kg/day subQ or IV over 15 to 30 minutes OR sargramostim 250 mcg/meter(2)/day IV over 4 hours.
    H) DRUG-INDUCED DYSTONIA
    1) ADULT: Benztropine 1 to 2 mg IV or diphenhydramine 1 mg/kg/dose IV over 2 minutes. CHILD: Diphenhydramine 1 mg/kg/dose IV over 2 minutes (maximum 5 mg/kg/day or 50 mg/m(2)/day).
    I) NEUROLEPTIC MALIGNANT SYNDROME
    1) Oral bromocriptine, benzodiazepines or oral or IV dantrolene in conjunction with cooling and other supportive measures.
    J) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    K) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    2) ADMISSION CRITERIA: Patients demonstrating persistent neurotoxicity should be admitted.
    3) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    L) PITFALLS
    1) When managing a suspected lurasidone overdose, the possibility of multidrug involvement should be considered.
    M) PHARMACOKINETICS
    1) Following ingestion, approximately 9% to 19% of the dose is absorbed. Approximately 99% bound to serum proteins. The mean apparent volume of distribution was 6173 L following ingestion of a single 40-mg dose. Metabolized primarily by CYP3A4 in the liver and biotransformation occurs by oxidative N-dealkylation, hydroxylation of the norbornane ring, and S-oxidation. Following the administration of a single oral [(14)C]-labeled lurasidone hydrochloride dose, approximately 9% of the radioactive dose was recovered in the urine and 80% was recovered in the feces. The mean elimination half-life was 18 hours following a single 40-mg dose.
    N) DIFFERENTIAL DIAGNOSIS
    1) Includes overdose of other atypical antipsychotic agents.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. During premarketing clinical studies, a patient ingested approximately 560 mg of lurasidone and recovered without sequelae. A man developed mild hypertension and elevated TSH (6.100 mIU/L) after ingesting 17 lurasidone 80 mg tablets (about 10.32 mg/kg; about 8.5 times the maximum recommended dose) and 5 clonazepam 1 mg tablets in a suicide attempt.
    B) THERAPEUTIC DOSE: ADULT: The recommended starting dose is 40 mg orally once daily. The dose may be increased up to a maximum daily dose of 80 mg. PEDIATRIC: Safety and efficacy have not been established in pediatric patients.

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Lurasidone an atypical antipsychotic indicated for the treatment of schizophrenia in adults. It is also indicated as either monotherapy or adjunctive therapy with lithium or valproate for the treatment of depressive episodes associated with bipolar I disorder in adults.
    B) PHARMACOLOGY: Lurasidone acts as an antagonist at dopamine type-2 (D2) and 5-hydroxytryptamine (5-HT)2A receptors. Lurasidone also has moderate antagonistic activity at alfa-2C and alfa-2A adrenergic receptors and is a partial agonist at 5-HT1A receptors. It exhibits minimal or no affinity for histamine type-1 (H1) or muscarinic type-1 (M1) receptors.
    C) TOXICOLOGY: Similar to other atypical antipsychotic agents in that it has a propensity to produce extrapyramidal effects. It does have alpha-1-adrenergic antagonist activity which may produce hypotension and other hemodynamic effects.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most common events reported with therapeutic use include somnolence, akathisia, nausea, parkinsonism, and agitation.
    2) INFREQUENT: Infrequent but potentially serious events include hypotension, neutropenia/leukopenia, hyperglycemia, tardive dyskinesia, and neuroleptic malignant syndrome.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Limited experience. During premarketing clinical trials, a patient ingested approximately 560 mg of lurasidone and recovered without sequelae. Elevated TSH and mild hypertension developed in a man after ingesting 17 lurasidone 80 mg tablets (about 10.32 mg/kg; about 8.5 times the maximum recommended dose).
    2) SEVERE POISONING: At the time of this review, there is no information on severe toxicity with lurasidone. Severe overdose might cause hypotension and altered mental status.
    0.2.20) REPRODUCTIVE
    A) Lurasidone is classified as FDA pregnancy category B. Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms with severity ranging from self-limiting cases to those requiring long periods of hospitalization and ICU care. Lurasidone has been shown to be excreted in the milk of lactating rats. In female rats, there was evidence of estrous cycle irregularities and reduced fertility following oral lurasidone exposure before and during mating.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for lurasidone in humans.

Clinical Effects

Summary Of Exposure

    A) USES: Lurasidone an atypical antipsychotic indicated for the treatment of schizophrenia in adults. It is also indicated as either monotherapy or adjunctive therapy with lithium or valproate for the treatment of depressive episodes associated with bipolar I disorder in adults.
    B) PHARMACOLOGY: Lurasidone acts as an antagonist at dopamine type-2 (D2) and 5-hydroxytryptamine (5-HT)2A receptors. Lurasidone also has moderate antagonistic activity at alfa-2C and alfa-2A adrenergic receptors and is a partial agonist at 5-HT1A receptors. It exhibits minimal or no affinity for histamine type-1 (H1) or muscarinic type-1 (M1) receptors.
    C) TOXICOLOGY: Similar to other atypical antipsychotic agents in that it has a propensity to produce extrapyramidal effects. It does have alpha-1-adrenergic antagonist activity which may produce hypotension and other hemodynamic effects.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most common events reported with therapeutic use include somnolence, akathisia, nausea, parkinsonism, and agitation.
    2) INFREQUENT: Infrequent but potentially serious events include hypotension, neutropenia/leukopenia, hyperglycemia, tardive dyskinesia, and neuroleptic malignant syndrome.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Limited experience. During premarketing clinical trials, a patient ingested approximately 560 mg of lurasidone and recovered without sequelae. Elevated TSH and mild hypertension developed in a man after ingesting 17 lurasidone 80 mg tablets (about 10.32 mg/kg; about 8.5 times the maximum recommended dose).
    2) SEVERE POISONING: At the time of this review, there is no information on severe toxicity with lurasidone. Severe overdose might cause hypotension and altered mental status.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ORTHOSTATIC HYPOTENSION
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, orthostatic hypotension occurred in 0.8% of patients treated with lurasidone 40 mg/day (n=360), in 1.4% of patients treated with 80 mg/day (n=282), and in 1.7% of patients treated with 120 mg/day (n=291) compared with 0.9% of placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).
    B) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 31-year-old man with a medical history of schizophrenia, obesity, and hypertension presented with mild hypertension (BP 140/87 mmHg) and an elevated TSH (6.100 mIU/L) 90 minutes after ingesting 17 lurasidone 80 mg tablets (about 10.32 mg/kg; about 8.5 times the maximum recommended dose) and 5 clonazepam 1 mg tablets in a suicide attempt. His hypertension resolved within 12 hours of ingestion. On a follow-up visit 3 weeks later, he had a normal TSH level (Molnar et al, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, somnolence occurred in 22% of patients treated with lurasidone at doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with 10% in placebo-treated patients (n=455). In short-term, fixed-dose, placebo-controlled trials, somnolence occurred in 15% of patients treated with 20 mg/day (n=71), in 19% of patients treated with 40 mg/day (n=360), in 23% of patients treated with 80 mg/day (n=282), and in 26% of patients treated with 120 mg/day (n=291) compared with 10% of placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).
    B) AKATHISIA
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, akathisia occurred in 15% of patients treated with lurasidone at doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with 3% in placebo-treated patients (n=455). In short-term, fixed-dose, placebo-controlled trials, akathisia occurred in 6% of patients treated with lurasidone 20 mg/day (n=71), in 11% of patients treated with 40 mg/day (n=360), in 15% of patients treated with 80 mg/day (n=282), and in 22% of patients treated with 120 mg/day (n=291) compared with 3% of placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).
    C) PARKINSONISM
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, parkinsonism (including these event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor) occurred in 11% of patients treated with lurasidone at doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with 5% in placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).
    D) TARDIVE DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Although infrequent, tardive dyskinesia has been reported with the use of lurasidone during premarketing clinical trials (Prod Info LATUDA(R) oral tablets, 2010).
    E) DYSTONIA
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, dystonia (including these event terms: oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus) occurred in 5% of patients treated with lurasidone at doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with less than 1% in placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).
    F) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, dizziness occurred in 5% of patients treated with lurasidone at doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with 3% in placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).
    G) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, insomnia occurred in 8% of patients treated with lurasidone at doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with 7% in placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).
    H) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) In short-term, placebo-controlled trials in patients with schizophrenia, all extrapyramidal (EPS) events occurred in 10% of patients treated with lurasidone 20 mg/day (n=71), in 24% of patients treated with 40 mg/day (n=360), in 26% of patients treated with 80 mg/day (n=282), and in 39% of patients treated with 120 mg/day (n=291) compared with 9% of placebo-treated patients (n=455). The incidence rates of all EPS events excluding akathisia and restlessness were 6%, 13%, 11%, and 22% for lurasidone 20, 40, 80, and 120 mg/day, respectively, compared with 5% of patients who received placebo. The proportions of patients who changed from normal to abnormal based on the Barnes Akathisia scale were 16% and 7.6% among lurasidone and placebo, respectively, and based on the SAS were 5.3% and 2.5%, respectively (Prod Info LATUDA(R) oral tablets, 2010).
    I) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH THERAPEUTIC USE
    a) Neuroleptic malignant syndrome (NMS) has been reported with the use of antipsychotic drugs, including lurasidone. Clinical manifestations may include hyperpyrexia, muscle rigidity, autonomic instability, elevated CPK levels, myoglobinuria, and acute renal failure (Prod Info LATUDA(R) oral tablets, 2010).
    J) PSYCHOMOTOR AGITATION
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, agitation and anxiety occurred in 6% of patients treated with lurasidone at doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with 3% in placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, nausea occurred in 12% of patients treated with lurasidone doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with 6% in placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).
    b) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, vomiting occurred in 8% of patients treated with lurasidone doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with 6% in placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).
    B) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, dyspepsia occurred in 8% of patients treated with lurasidone doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with 6% in placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).
    C) EXCESSIVE SALIVATION
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, salivary hypersecretion occurred in 2% of patients treated with lurasidone doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with less than 1% in placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported with the use of antipsychotic agents, including lurasidone (Prod Info LATUDA(R) oral tablets, 2010).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia has been reported with the use of antipsychotic agents, including lurasidone. In patients with an absolute neutrophil count of less than 1000/mm(3), therapy should be discontinued and serial WBC counts should be monitored until recovery occurs (Prod Info LATUDA(R) oral tablets, 2010).
    C) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Agranulocytosis, including fatal outcomes, has been associated with antipsychotic agents in this class (Prod Info LATUDA(R) oral tablets, 2010). At the time of this review, it has not been reported with lurasidone.

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In pooled data from short-term, placebo-controlled trials in patients with schizophrenia, back pain occurred in 4% of patients treated with lurasidone at doses ranging from 20 mg to 120 mg orally daily (n=1004) compared with 3% in placebo-treated patients (n=455) (Prod Info LATUDA(R) oral tablets, 2010).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERPROLACTINEMIA
    1) WITH THERAPEUTIC USE
    a) In short-term, placebo-controlled trials of lurasidone, the median change from baseline to endpoint in prolactin levels was -1.1 nanogram/mL (ng/L) in those who received lurasidone compared with -0.6 ng/mL in those who received placebo. The median change from baseline to endpoint was greater in females (1.5 ng/mL) compared with males (1.1 ng/mL) (Prod Info LATUDA(R) oral tablets, 2010).
    B) IMPAIRED FASTING GLYCAEMIA
    1) WITH THERAPEUTIC USE
    a) In short-term, placebo-controlled trials in patients with schizophrenia, the mean change in fasting glucose (mg/dL) from baseline was -0.6, 2.5, -0.9, and 2.5 in patients who received lurasidone 20 mg/day (n=71), 40 mg/day (n=352), 80 mg/day (n=270), and 120 mg/day (n=283), respectively, compared with -0.7 in patients who received placebo (n=438). The proportion of patients with a shift in fasting glucose to 126 mg/dL or greater was 11.7%, 14.3%, 10%, and 10% of patients who received lurasidone 20 mg/day (n=60), 40 mg/day (n=328), 80 mg/day (n=241), and 120 mg/day (n=260), respectively, compared with 8.6% of patients who received placebo (n=397) (Prod Info LATUDA(R) oral tablets, 2010).
    b) In the primarily open-label extension studies, which were uncontrolled and longer-term studies, treatment with lurasidone was associated with a mean change in glucose of 1.6 mg/dL, 0.3 mg/dL, and 1.2 mg/dL at week 24 (n=186), week 36 (n=236), and week 52 (n=244), respectively (Prod Info LATUDA(R) oral tablets, 2010).
    C) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia, including cases associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving antipsychotic agents in this class (Prod Info LATUDA(R) oral tablets, 2010). At the time of this review, it has not been reported with lurasidone.
    D) THYROID FUNCTION TESTS ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 31-year-old man with a medical history of schizophrenia, obesity, and hypertension presented with mild hypertension (BP 140/87 mmHg) and an elevated TSH (6.100 mIU/L) 90 minutes after ingesting 17 lurasidone 80 mg tablets (about 10.32 mg/kg; about 8.5 times the maximum recommended dose) and 5 clonazepam 1 mg tablets in a suicide attempt. His hypertension resolved within 12 hours of ingestion. On a follow-up visit 3 weeks later, he had a normal TSH level (Molnar et al, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Lurasidone is classified as FDA pregnancy category B. Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms with severity ranging from self-limiting cases to those requiring long periods of hospitalization and ICU care. Lurasidone has been shown to be excreted in the milk of lactating rats. In female rats, there was evidence of estrous cycle irregularities and reduced fertility following oral lurasidone exposure before and during mating.
    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 lurasidone (Prod Info LATUDA(R) oral tablets, 2012).
    B) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) There was no evidence of teratogenicity when pregnant rats and rabbits were given lurasidone at doses up to 25 and 50 mg/kg/day (1.5 and 6 times the maximum recommended human dose (MRHD) of 160 mg/day based on body surface area), respectively, during the period of organogenesis. There were also no adverse developmental effects when pregnant rats were given lurasidone at doses up to 10 mg/kg/day (approximately one-half the MRHD) (Prod Info LATUDA(R) oral tablets, 2012).
    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 lurasidone during pregnancy in humans (Prod Info LATUDA(R) oral tablets, 2012).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified lurasidone as FDA pregnancy category B (Prod Info LATUDA(R) oral tablets, 2012).
    C) WITHDRAWAL SYMPTOMS
    1) Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms (eg, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) following delivery. Severity of these adverse effects have ranged from cases that are self-limiting to cases that required prolonged periods of hospitalization and ICU care (Prod Info LATUDA(R) oral tablets, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to lurasidone during lactation in humans (Prod Info LATUDA(R) oral tablets, 2012).
    B) ANIMAL STUDIES
    1) Lurasidone was shown to be excreted in the milk of lactating rats (Prod Info LATUDA(R) oral tablets, 2012).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility in humans from exposure to lurasidone (Prod Info LATUDA(R) oral tablets, 2012).
    B) ANIMAL STUDIES
    1) FEMALE RATS: There was evidence of estrous cycle irregularities when female rats were given lurasidone doses of 1.5 mg/kg/day and higher for 15 consecutive days before mating, during mating, and through gestation day 7. The no-effect dose was 0.1 mg/kg (approximately 0.006 times the maximum recommended human dose (MRHD) of 160 mg/day based on body surface area). Decreased fertility was observed at the highest dose of 150 mg/kg/day, but was shown to be reversible after 14 days of being off lurasidone. Reduced fertility had a no-effect dose of 15 mg/kg (approximately equal to the MRHD) (Prod Info LATUDA(R) oral tablets, 2012).
    2) MALE RATS: There was no evidence of adverse effects on fertility when male rats were given oral lurasidone at doses up to 150 mg/kg/day (9 times the MRHD based on body surface area) for 64 consecutive days before mating and during the mating period (Prod Info LATUDA(R) oral tablets, 2012).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for lurasidone in humans.
    3.21.4) ANIMAL STUDIES
    A) MAMMARY GLAND CARCINOMAS
    1) FEMALE MICE: There were increased incidences of malignant mammary gland tumors when female mice were given oral lurasidone at doses of 30, 100, 300, or 650 mg/kg/day in lifetime carcinogenicity studies. The AUC at the lowest dose was approximately equal to that of humans treated with the maximum recommended human dose (MRHD) of 160 mg/day (Prod Info LATUDA(R) oral tablets, 2012).
    2) FEMALE RATS: There were increased incidences of mammary gland carcinomas at the 2 highest doses when female rats were given oral lurasidone at doses of 3, 12, or 36 mg/kg/day in lifetime carcinogenicity studies. The AUC at the no-effect dose of 3 mg/kg/day was 0.4 times that of humans treated with the maximum recommended human dose (MRHD) of 160 mg/day (Prod Info LATUDA(R) oral tablets, 2012).
    3) There has been an increased frequency of mammary gland proliferation and/or neoplasms in rodents following chronic exposure to other antipsychotic agents; the changes are believed to be prolactin-mediated. The relevance for human risk of the prolactin-mediated mammary gland tumors is unknown (Prod Info LATUDA(R) oral tablets, 2012).
    B) PITUITARY GLAND ADENOMAS
    1) FEMALE MICE: There were increased incidences of pituitary gland adenomas when female mice were given oral lurasidone at doses of 30, 100, 300, or 650 mg/kg/day in lifetime carcinogenicity studies. The AUC at the lowest dose was approximately equal to that of humans treated with the maximum recommended human dose (MRHD) of 160 mg/day (Prod Info LATUDA(R) oral tablets, 2012).
    2) There has been an increased frequency of pituitary gland proliferation and/or neoplasms in rodents following chronic exposure to other antipsychotic agents; the changes are believed to be prolactin-mediated. The relevance for human risk of the prolactin-mediated pituitary gland tumors is unknown (Prod Info LATUDA(R) oral tablets, 2012).
    C) LACK OF EFFECT
    1) MALE MICE: There were no increases in the incidence of tumors at the highest dose tested when male mice were given oral lurasidone at doses of 30, 100, 300, or 650 mg/kg/day in lifetime carcinogenicity studies. The AUC at the highest dose tested was 14 times that of humans treated with the maximum recommended human dose (MRHD) of 160 mg/day (Prod Info LATUDA(R) oral tablets, 2012).
    2) MALE RATS: There were no increases in the incidence of tumors at the highest dose tested when male rats were given oral lurasidone at doses of 3, 12, or 36 mg/kg/day in lifetime carcinogenicity studies. The AUC at the highest dose tested was 6 times that of humans treated with the maximum recommended human dose (MRHD) of 160 mg/day (Prod Info LATUDA(R) oral tablets, 2012).

Genotoxicity

    A) There was no evidence of genotoxicity at doses up to 2000 mg/kg (61 times the maximum recommended human dose (MRHD) of 160 mg/day based on body surface area) in the following tests: Ames test, in vitro chromosomal aberration test in Chinese hamster lung cells, or the in vivo mouse bone marrow micronucleus test (Prod Info LATUDA(R) oral tablets, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Lurasidone plasma concentrations are not readily available or clinically useful in the treatment of overdose.
    C) Obtain a baseline ECG and repeat as needed; continuous cardiac monitoring may be necessary in symptomatic patients.
    D) Routine laboratory studies are not likely to be necessary.
    4.1.2) SERUM/BLOOD
    A) Lurasidone plasma concentrations are not readily available or clinically useful in the treatment of overdose.
    B) Routine laboratory studies are not likely to be necessary.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs and mental status.
    b) Obtain a baseline ECG and repeat as needed; continuous cardiac monitoring may be necessary in symptomatic patients.

Treatment

Monitoring

    A) Monitor vital signs and mental status.
    B) Lurasidone plasma concentrations are not readily available or clinically useful in the treatment of overdose.
    C) Obtain a baseline ECG and repeat as needed; continuous cardiac monitoring may be necessary in symptomatic patients.
    D) Routine laboratory studies are not likely to be necessary.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Activated charcoal is not recommended due to the potential for somnolence or dystonic reactions 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) SUPPORT
    1) Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Lurasidone plasma concentrations are not readily available or clinically useful in the treatment of overdose.
    3) Obtain a baseline ECG and repeat as needed; continuous cardiac monitoring may be necessary in symptomatic patients.
    4) Routine laboratory studies are not likely to be necessary.
    C) HYPOTENSIVE EPISODE
    1) Treat hypotension with intravenous fluids; add vasopressors if unresponsive to fluids. Norepinephrine is preferred; the manufacturer recommends avoidance of epinephrine and dopamine since beta stimulation may worsen hypotension in the setting of lurasidone-induced alpha blockade (Prod Info LATUDA(R) oral tablets, 2010).
    2) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) NEUTROPENIA
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    E) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    F) NEUROLEPTIC MALIGNANT SYNDROME
    1) May be successfully managed diphenhydramine, oral bromocriptine, benzodiazepines, or intravenous or oral dantrolene sodium in conjunction with cooling and other supportive care (May et al, 1983; Mueller et al, 1983; Leikin et al, 1987; Schneider, 1991; Barkin, 1992).
    a) 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).
    1) DIAZEPAM DOSE: 3 to 5 mg intravenous bolus to slow push initially, followed by 1 to 2.5 mg intravenously in 10 minutes.
    b) BROMOCRIPTINE DOSE: 5 mg three times a day orally (Mueller et al, 1983).
    c) DANTROLENE LOADING DOSE: 2.5 mg/kg, to a maximum of 10 mg/kg intravenously (Barkin, 1992).
    d) DANTROLENE MAINTENANCE DOSE: 2.5 mg/kg intravenously 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).
    1) 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).
    2) Some studies report NO beneficial effects and suggest that dantrolene might even worsen the course of NMS (Rosebush & Stewart, 1989).
    e) 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).
    2) 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).
    a) The time to complete resolution was also shorter with these therapeutic interventions (Rosenberg & Green, 1989).
    3) 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 (Sakkas et al, 1991).
    a) 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).
    b) 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.

Enhanced Elimination

    A) LACK OF EFFECT
    1) Hemodialysis and hemoperfusion are UNLIKELY to be useful in a lurasidone overdose because of the high degree of protein binding and large volume of distribution.

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 with deliberate ingestions demonstrating persistent neurotoxicity should be admitted.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. During premarketing clinical studies, a patient ingested approximately 560 mg of lurasidone and recovered without sequelae. A man developed mild hypertension and elevated TSH (6.100 mIU/L) after ingesting 17 lurasidone 80 mg tablets (about 10.32 mg/kg; about 8.5 times the maximum recommended dose) and 5 clonazepam 1 mg tablets in a suicide attempt.
    B) THERAPEUTIC DOSE: ADULT: The recommended starting dose is 40 mg orally once daily. The dose may be increased up to a maximum daily dose of 80 mg. PEDIATRIC: Safety and efficacy have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) SCHIZOPHRENIA
    1) Initially, 40 mg orally once daily. MAXIMUM DOSE: 160 mg/day (Prod Info LATUDA(R) oral tablets, 2012).
    B) DEPRESSIVE EPISODES IN BIPOLAR DISORDER
    1) Initially, 20 mg orally once daily as monotherapy or adjunctive therapy with lithium or valproate; initial dose titration not required. MAXIMUM DOSE: 120 mg once daily; long-term usefulness beyond 6 weeks should be periodically re-evaluated (Prod Info LATUDA(TM) oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) Safety and efficacy of lurasidone have not been established in pediatric patients (Prod Info LATUDA(R) oral tablets, 2012).

Maximum Tolerated Exposure

    A) During premarketing clinical trials, a patient ingested approximately 560 mg of lurasidone and recovered without sequelae (Prod Info LATUDA(R) oral tablets, 2010).
    B) CASE REPORT: A 31-year-old man with a medical history of schizophrenia, obesity, and hypertension presented with mild hypertension (BP 140/87 mmHg) and an elevated TSH (6.100 mIU/L) 90 minutes after ingesting 17 lurasidone 80 mg tablets (about 10.32 mg/kg; about 8.5 times the maximum recommended dose) and 5 clonazepam 1 mg tablets in a suicide attempt. His hypertension resolved within 12 hours of ingestion. On a follow-up visit 3 weeks later, he had a normal TSH level (Molnar et al, 2014).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Lurasidone is an atypical antipsychotic agent that acts as an antagonist at dopamine type-2 (D2) and 5-hydroxytryptamine (5-HT)2A receptors. Lurasidone also has moderate antagonistic activity at alfa-2C and alfa-2A adrenergic receptors and is a partial agonist at 5-HT1A receptors. It exhibits minimal or no affinity for histamine type-1 (H1) or muscarinic type-1 (M1) receptors (Prod Info LATUDA(R) oral tablets, 2010).

Physicochemical

Physical Characteristics

    A) Lurasidone hydrochloride is a white to off-white powder that is slightly soluble in ethanol, very slightly soluble in water or acetone, sparingly soluble in methanol, and practically insoluble or insoluble in 0.1 N hydrochloride solution or toluene (Prod Info LATUDA(R) oral tablets, 2010).

Molecular Weight

    A) 529.14 (Prod Info LATUDA(R) oral tablets, 2010)

References

General Bibliography

    1) Barkin RM: Pediatric Emergency Medicine, Mosby YearBook, St Louis, MO, 1992, pp 500.
    2) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    3) Blue MG, Schneider SM, & Noro S: Successful treatment of neuroleptic malignant syndrome with sodium nitroprusside. Ann Intern Med 1986; 104:56-57.
    4) Caroff SN & Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 1993; 77:185-203.
    5) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    6) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    7) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    8) Goldfrank L, Flomenbaum N, Lewin N, et al (Eds): Goldfrank's Toxicologic Emergencies, 7th ed. McGraw-Hill, New York, NY, 2002.
    9) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    10) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    11) Granato JE, Stern BJ, & Ringel A: Neuroleptic malignant syndrome: successful treatment with dantrolene and bromocriptine. Ann Neurol 1983; 14:89-90.
    12) Gratz SS, Levinson DF, & Simpson GM: The treatment and management of neuroleptic malignant syndrome. Prog Neuro-Psychopharmacol Biol Psychiat 1992; 16:425-443.
    13) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    14) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    15) 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.
    16) Knight ME & Roberts RJ: Phenothiazine and butyrophenone intoxication in children. Pediatr Clin North Am 1986; 33:299-309.
    17) Leikin JB, Baron S, & Engle J: Treatment of neuroleptic malignant syndrome with diphenhydramine (abstract). Vet Hum Toxicol 1987; 29:480.
    18) May DC, Morris SW, & Stewart RW: Neuroleptic malignant syndrome: response to dantrolene sodium. Ann Intern Med 1983; 98:183-184.
    19) Molnar GP, Grimsich LC, Catalano G, et al: Acute lurasidone overdose. J Clin Psychopharmacol 2014; 34(6):768-770.
    20) Mueller PS, Vester JW, & Fermaglich J: Neuroleptic malignant syndrome: successful treatment with bromocriptine. JAMA 1983; 249:386-388.
    21) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    22) 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.
    23) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
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    25) Product Information: LATUDA(R) oral tablets, lurasidone HCl oral tablets. Sunovion Pharmaceuticals Inc., Fort Lee, NJ, 2010.
    26) Product Information: LATUDA(TM) oral tablets, lurasidone HCl oral tablets. Sunovion Pharmaceuticals, Inc. (per manufacturer), Marlborough, MA, 2013.
    27) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    28) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    29) Product Information: benztropine mesylate IV, IM injection, benztropine mesylate IV, IM injection. West-ward Pharmaceutical Corp, Eatontown, NJ, 2009.
    30) Product Information: diphenhydramine hcl injection, diphenhydramine hcl injection. Bioniche Pharma USA,LLC, Lake Forest, IL, 2006.
    31) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    32) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    33) Rosebush P & Stewart T: A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry 1989; 146:717-725.
    34) Rosenberg MR & Green M: Neuroleptic malignant syndrome: Review of response to therapy. Arch Intern Med 1989; 149:1927-1931.
    35) Sakkas P, Davis JM, & Janicak PG: Drug treatment of the neuroleptic malignant syndrome. Psychopharmacol Bull 1991; 27:381-384.
    36) Schneider SM: Neuroleptic malignant syndrome: controversies in treatment. Am J Emerg Med 1991; 9:360-362.
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