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VORTIOXETINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Vortioxetine, an antidepressant, inhibits the reuptake of serotonin (5-HT), is an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors, is an agonist at 5-HT1A receptors, and is a 5-HT1B receptor partial agonist. It is indicated for the treatment of major depressive disorder in adults.

Specific Substances

    1) Vortioxetine Hydrobromide
    2) 508233-74-7 (CAS)
    1.2.1) MOLECULAR FORMULA
    1) C18-H22-N2-S, HBr (vortioxetine hydrobromide) (Prod Info TRINTELLIX oral tablets, 2016)

Available Forms Sources

    A) FORMS
    1) Vortioxetine is available as 5 mg, 10 mg, 15 mg, and 20 mg immediate-release film-coated tablets (Prod Info TRINTELLIX oral tablets, 2016).
    2) NOTE/BRAND NAME CHANGE: The US FDA has approved a brand name change for the antidepressant Brintellix (vortioxetine) to decrease the risk of prescribing and dispensing errors resulting from name confusion with the blood-thinning medicine Brilinta (ticagrelor). The new brand name will be Trintellix, and anticipated to be available in June 2016. No other changes will be made to the label or packaging, and the medication will be exactly the same.
    B) USES
    1) Vortioxetine is indicated for the treatment of major depressive disorder in adults (Prod Info TRINTELLIX oral tablets, 2016).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Vortioxetine is a serotonergic antidepressant indicated for the treatment of major depressive disorder in adults.
    B) PHARMACOLOGY: Inhibits the reuptake of serotonin (5-HT), is an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors, an agonist at 5-HT1A receptors, and is a partial agonist of the 5-HT1B receptor.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse reactions following therapeutic administration, with an incidence rate of at least 5% and at least twice the rate of placebo, include nausea, vomiting, and constipation.
    2) LESS FREQUENT: Adverse reactions that have occurred less frequently include: hyponatremia, dry mouth, diarrhea, dyspepsia, flatulence, dizziness, pruritus, flushing, somnolence, and abnormal dreams. Serotonin syndrome (hyperreflexia, clonus, altered mental status, hemodynamic instability) has been reported with the use of vortioxetine alone and with the concurrent use of other serotonergic drugs.
    3) Withdrawal symptoms, following abrupt cessation of vortioxetine therapy, may include headache, muscle tension, dizziness, rhinorrhea, mood swings, and angry outbursts.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic adverse events. Ingestions of 40 to 75 mg have resulted in increased incidences of nausea, dizziness, abdominal discomfort, generalized pruritus, somnolence and flushing.
    0.2.20) REPRODUCTIVE
    A) Vortioxetine is classified as FDA pregnancy category C. Although there are no adequate or well-controlled studies of vortioxetine in pregnant women, developmental delays of offspring have been reported following maternal administration of vortioxetine during animal studies.

Laboratory Monitoring

    A) Monitor vital signs (including temperature) and mental status.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Vortioxetine plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is generally symptomatic and supportive. Treat serotonin toxicity with benzodiazepines and consider cyproheptadine, if symptoms persist. Severe cases may require neuromuscular paralysis.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is alert, not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is alert, not vomiting, and is able to maintain airway. Gastric lavage is not recommended as overdose is rarely life threatening.
    D) AIRWAY MANAGEMENT
    1) Perform early with neuromuscular paralysis if the patient presents with respiratory or CNS depression, severe muscle rigidity, or severe hyperthermia.
    E) ANTIDOTE
    1) There is no antidote.
    F) SEROTONIN SYNDROME
    1) Treat initially with benzodiazepines. Cyproheptadine is sometimes used for moderate cases. Patients with severe serotonin syndrome (ie, severe hyperthermia, agitation, rigidity, hypertension, tachycardia, acidosis) may require neuromuscular paralysis.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with a small inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) Failure to aggressively control agitation, muscle rigidity, and hyperthermia with adequate benzodiazepines, intubation with neuromuscular paralysis and body cooling. Consider the possibility of ingestion of multiple substances. Patients who are taking another agent that increases CNS serotonin are more likely to develop serotonin syndrome.
    J) PHARMACOKINETICS
    1) Absolute bioavailability is 75%. Protein binding is 98%; extensively distributed into extravascular space, with an apparent volume of distribution of approximately 2600 L. Primarily renally excreted as metabolites. Terminal half-life is approximately 66 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Differential diagnosis may include many other agents given the unspecific signs and symptoms of vortioxetine overdose. Evaluate patient for serotonin toxicity.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Overdose ingestions of 40 to 75 mg have been associated with increased incidences of nausea, dizziness, abdominal discomfort, generalized pruritus, flushing, and somnolence.
    B) THERAPEUTIC DOSE: The recommended starting dose is 10 mg orally once daily, and may be increased to 20 mg/day as tolerated.

Clinical Effects

Summary Of Exposure

    A) USES: Vortioxetine is a serotonergic antidepressant indicated for the treatment of major depressive disorder in adults.
    B) PHARMACOLOGY: Inhibits the reuptake of serotonin (5-HT), is an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors, an agonist at 5-HT1A receptors, and is a partial agonist of the 5-HT1B receptor.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse reactions following therapeutic administration, with an incidence rate of at least 5% and at least twice the rate of placebo, include nausea, vomiting, and constipation.
    2) LESS FREQUENT: Adverse reactions that have occurred less frequently include: hyponatremia, dry mouth, diarrhea, dyspepsia, flatulence, dizziness, pruritus, flushing, somnolence, and abnormal dreams. Serotonin syndrome (hyperreflexia, clonus, altered mental status, hemodynamic instability) has been reported with the use of vortioxetine alone and with the concurrent use of other serotonergic drugs.
    3) Withdrawal symptoms, following abrupt cessation of vortioxetine therapy, may include headache, muscle tension, dizziness, rhinorrhea, mood swings, and angry outbursts.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic adverse events. Ingestions of 40 to 75 mg have resulted in increased incidences of nausea, dizziness, abdominal discomfort, generalized pruritus, somnolence and flushing.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In pooled data from multiple 6-to-8-week controlled studies of adults with major depressive disorder, dizziness occurred in 6% of patients treated with a vortioxetine 5 mg/day dose (n=1013), 6% of patients treated with a 10 mg/day dose (n=699), 8% of patients treated with a 15 mg/day dose (n=449), and 9% of patients treated with a 20 mg/day dose (n=455) compared with 6% of placebo-treated patients (n=1621) (Prod Info TRINTELLIX oral tablets, 2016).
    2) WITH POISONING/EXPOSURE
    a) An increased incidence of dizziness has been associated with vortioxetine overdose ingestions of 40 to 75 mg (Prod Info TRINTELLIX oral tablets, 2016).
    B) SEROTONIN SYNDROME
    1) WITH THERAPEUTIC USE
    a) Serotonin syndrome has been reported with the use of vortioxetine alone and with the concurrent use of other serotonergic drugs (eg, tricyclic antidepressants, triptans, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's wort) and drugs that inhibit serotonin metabolism (eg, MAOIs intended to treat psychiatric disorders as well as methylene blue IV and linezolid) (Prod Info TRINTELLIX oral tablets, 2016).
    C) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Somnolence has been associated with vortioxetine overdose ingestions of 40 to 75 mg (Prod Info TRINTELLIX oral tablets, 2016).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea was the most common adverse reaction (and the most common reason for treatment discontinuation) during multiple 6-to-8-week controlled studies of vortioxetine treatment of adults with major depressive disorder. Nausea occurred in 21% of patients treated with a vortioxetine 5 mg/day dose (n=1013), 26% of patients treated with a 10 mg/day dose (n=699), 32% of patients treated with a 15 mg/day dose (n=449), and 32% of patients treated with a 20 mg/day dose (n=455) compared with 9% of placebo-treated patients (n=1621). More common in women, nausea was usually rated mild to moderate in intensity, with a median duration of 2 weeks. Between 15% and 20% of vortioxetine-treated patients developed nausea 1 to 2 days after treatment initiation. Nausea remained an active complaint in about 10% of patients receiving vortioxetine 10 mg to 20 mg/day at the end of the 6- to 8-week study period (Prod Info TRINTELLIX oral tablets, 2016).
    b) In pooled data from multiple 6-to-8-week controlled studies of adults with major depressive disorder, vomiting occurred in 3% of patients treated with a vortioxetine 5 mg/day dose (n=1013), 5% of patients treated with a 10 mg/day dose (n=699), 6% of patients treated with a 15 mg/day dose (n=449), and 6% of patients treated with a 20 mg/day dose (n=455) compared with 1% of placebo-treated patients (n=1621) (Prod Info TRINTELLIX oral tablets, 2016).
    2) WITH POISONING/EXPOSURE
    a) An increased incidence of nausea has been associated with vortioxetine overdose ingestions of 40 to 75 mg (Prod Info TRINTELLIX oral tablets, 2016).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In pooled data from multiple 6-to-8-week controlled studies of adults with major depressive disorder, diarrhea occurred in 7% of patients treated with a vortioxetine 5 mg/day dose (n=1013), 7% of patients treated with a 10 mg/day dose (n=699), 10% of patients treated with a 15 mg/day dose (n=449), and 7% of patients treated with a 20 mg/day dose (n=455) compared with 6% of placebo-treated patients (n=1621) (Prod Info TRINTELLIX oral tablets, 2016).
    2) WITH POISONING/EXPOSURE
    a) An increased incidence of diarrhea has been associated with vortioxetine overdose ingestions of 40 to 75 mg (Prod Info TRINTELLIX oral tablets, 2016).
    C) APTYALISM
    1) WITH THERAPEUTIC USE
    a) In pooled data from multiple 6-to-8-week controlled studies of adults with major depressive disorder, dry mouth occurred in 7% of patients treated with a vortioxetine 5 mg/day dose (n=1013), 7% of patients treated with a 10 mg/day dose (n=699), 6% of patients treated with a 15 mg/day dose (n=449), and 8% of patients treated with a 20 mg/day dose (n=455) compared with 6% of placebo-treated patients (n=1621) (Prod Info TRINTELLIX oral tablets, 2016).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In pooled data from multiple 6-to-8-week controlled studies of adults with major depressive disorder, constipation occurred in 3% of patients treated with a vortioxetine 5 mg/day dose (n=1013), 5% of patients treated with a 10 mg/day dose (n=699), 6% of patients treated with a 15 mg/day dose (n=449), and 6% of patients treated with a 20 mg/day dose (n=455) compared with 3% of placebo-treated patients (n=1621) (Prod Info TRINTELLIX oral tablets, 2016).
    E) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) In pooled data from multiple 6-to-8-week controlled studies of adults with major depressive disorder, flatulence occurred in 1% of patients treated with a vortioxetine 5 mg/day dose (n=1013), 3% of patients treated with a 10 mg/day dose (n=699), 2% of patients treated with a 15 mg/day dose (n=449), and 1% of patients treated with a 20 mg/day dose (n=455) compared with 1% of placebo-treated patients (n=1621) (Prod Info TRINTELLIX oral tablets, 2016).
    F) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dyspepsia has been reported with vortioxetine therapy at a higher incidence than placebo (Prod Info TRINTELLIX oral tablets, 2016).
    2) WITH POISONING/EXPOSURE
    a) An increased incidence of abdominal discomfort has been associated with vortioxetine overdose ingestions of 40 to 75 mg (Prod Info TRINTELLIX oral tablets, 2016).
    G) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) Dysgeusia has been reported with vortioxetine therapy at a higher incidence than placebo (Prod Info BRINTELLIX oral tablets, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In pooled data from multiple 6-to-8-week controlled studies of adults with major depressive disorder, pruritus (including generalized pruritus) occurred in 1% of patients treated with a vortioxetine 5 mg/day dose (n=1013), 2% of patients treated with a 10 mg/day dose (n=699), 3% of patients treated with a 15 mg/day dose (n=449), and 3% of patients treated with a 20 mg/day dose (n=455) compared with 1% of placebo-treated patients (n=1621) (Prod Info TRINTELLIX oral tablets, 2016).
    2) WITH POISONING/EXPOSURE
    a) An increased incidence of generalized pruritus has been associated with vortioxetine overdose ingestions of 40 to 75 mg (Prod Info TRINTELLIX oral tablets, 2016).
    B) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Flushing has been reported with vortioxetine therapy at a higher incidence than placebo (Prod Info TRINTELLIX oral tablets, 2016).
    2) WITH POISONING/EXPOSURE
    a) An increased incidence of flushing has been associated with vortioxetine overdose ingestions of 40 to 75 mg (Prod Info TRINTELLIX oral tablets, 2016).

Reproductive

    3.20.1) SUMMARY
    A) Vortioxetine is classified as FDA pregnancy category C. Although there are no adequate or well-controlled studies of vortioxetine in pregnant women, developmental delays of offspring have been reported following maternal administration of vortioxetine during animal studies.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT: During animal studies, no teratogenic effects were observed in pregnant rats and rabbits administered vortioxetine up to 160 and 60 mg/kg/day, respectively (approximately 77 and 58 times the maximum recommended human dose (MRHD) (20 mg) on a mg/m(2) basis, respectively), during organogenesis (Prod Info TRINTELLIX oral tablets, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Vortioxetine is classified as FDA pregnancy category C (Prod Info TRINTELLIX oral tablets, 2016).
    B) AUTISM SPECTRUM DISORDER
    1) A cohort study of prospectively collected data demonstrated an increased risk of autism spectrum disorder (ASD) in children whose mothers used antidepressants during the second or third trimesters of pregnancy; the risk was even greater with second or third trimester exposure to SSRIs. Thirty-one infants who were exposed to antidepressants during the second or third trimester were diagnosed with ASD. After adjusting for potential confounders, second or third trimester exposure to antidepressants was associated with a significant 87% increased risk of ASD, while first trimester exposure or use of antidepressants in the year before pregnancy was not associated with any such risk. Use of SSRIs during the second or third trimester was associated with a significant more than 2-fold increased risk of ASD (22 exposed infants), while other classes of antidepressants were not associated with an increased risk. Even after restricting the sample size to those children whose mothers had a history of depression and used antidepressants during the second or third trimester, the risk of ASD still persisted. In addition, use of more than 1 class of antidepressants during the second or third trimester was associated with a significant more than 4-fold increased risk of ASD (Boukhris et al, 2016).
    C) ANIMAL STUDIES
    1) At vortioxetine doses greater than or equal to 30 and 10 mg/kg (approximately 15 and 10 times the MRHD, respectively) in rats and rabbits, respectively, developmental delays, including decreased fetal body weight and delayed ossification, were reported. Maternal toxicity, defined as decreased food consumption and decreased body weight gain, was also reported. Administration of vortioxetine 40 and 120 mg/kg in pregnant rats during pregnancy and lactation resulted in increased early postnatal pup mortality and delayed eye opening; at 120 mg/kg (58 times the MRHD), the number of live-born pups decreased and pup weights were decreased at birth to weaning (Prod Info TRINTELLIX oral tablets, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) Lactation studies with vortioxetine have not been conducted. It is unknown whether vortioxetine is excreted into human milk (Prod Info TRINTELLIX oral tablets, 2016).
    B) ANIMAL STUDIES
    1) RATS: Vortioxetine is present in the milk of lactating rats (Prod Info TRINTELLIX oral tablets, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT: There were no effects on male or female fertility in rats who were given vortioxetine at doses up to 120 mg/kg/day (58 times the maximum recommended human dose of 20 mg on a mg/m(2) basis) (Prod Info TRINTELLIX oral tablets, 2016).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) BENIGN ADENOMA
    1) A statistically significant increased incidence of benign polypoid adenomas of the rectum were reported in female mice, during 2-year carcinogenicity studies, who were given vortioxetine at doses up to 80 mg/kg/day (approximately 39 times the MRHD). The adenomas were associated with inflammation and hyperplasia, and may have been due to an interaction with the vehicle component within the formulation that was used for the study (Prod Info TRINTELLIX oral tablets, 2016).
    B) LACK OF EFFECT
    1) During 2-year carcinogenicity studies, there was no evidence of carcinogenicity in male rats at vortioxetine doses up to 40 mg/kg/day (approximately 20 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m(2) basis) or in male and female mice at doses up to 50 and 100 mg/kg/day, respectively (approximately 12 and 24 times, respectively, the MRHD) (Prod Info TRINTELLIX oral tablets, 2016).

Genotoxicity

    A) Vortioxetine was not genotoxic in the in vitro chromosome aberration assay in cultured human lymphocytes, in the in vitro bacterial reverse mutation assay (Ames test), and in the in vivo rat bone marrow micronucleus assay (Prod Info TRINTELLIX oral tablets, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs (including temperature) and mental status.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Vortioxetine plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs (including temperature) and mental status.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Vortioxetine plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) 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).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is generally symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) AIRWAY MANAGEMENT
    1) Perform early with neuromuscular paralysis if the patient presents with respiratory or CNS depression, severe muscle rigidity, or severe hyperthermia.
    C) MONITORING OF PATIENT
    1) Monitor vital signs (including temperature) and mental status.
    2) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    3) Vortioxetine plasma concentrations are not readily available or clinically useful in the management of overdose.
    D) SEROTONIN SYNDROME
    1) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    2) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    3) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    4) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    5) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    6) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    7) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    8) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Overdose ingestions of 40 to 75 mg have been associated with increased incidences of nausea, dizziness, abdominal discomfort, generalized pruritus, flushing, and somnolence.
    B) THERAPEUTIC DOSE: The recommended starting dose is 10 mg orally once daily, and may be increased to 20 mg/day as tolerated.

Therapeutic Dose

    7.2.1) ADULT
    A) INITIAL DOSE: The recommended starting dose is 10 mg/day orally (Prod Info TRINTELLIX oral tablets, 2016).
    B) MAINTENANCE DOSE: The recommended maintenance dose is 20 mg/day orally (Prod Info TRINTELLIX oral tablets, 2016).
    7.2.2) PEDIATRIC
    A) Safety and efficacy have not been established in pediatric patients (Prod Info TRINTELLIX oral tablets, 2016).

Maximum Tolerated Exposure

    A) A specific toxic dose has not been established. Overdose ingestions of 40 to 75 mg have been associated with increased incidences of nausea, dizziness, abdominal discomfort, generalized pruritus, flushing, and somnolence (Prod Info TRINTELLIX oral tablets, 2016).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Vortioxetine is a serotonergic antidepressant that inhibits the reuptake of serotonin (5-HT), is an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors, an agonist at 5-HT1A receptors, and is a partial agonist of the 5-HT1B receptor. The contribution of vortioxetine's activities at serotonin receptor subtypes to the clinical antidepressant effects has not been established (Prod Info TRINTELLIX oral tablets, 2016).

Physicochemical

Physical Characteristics

    A) Vortioxetine hydrobromide is a white to beige powder that is slightly soluble in water (Prod Info TRINTELLIX oral tablets, 2016).

Molecular Weight

    A) 379.36 g/mol (vortioxetine hydrobromide)(Prod Info TRINTELLIX oral tablets, 2016)

References

General Bibliography

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