FLUVOXAMINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) DU-23000
2) Fluvoksamiinimaleaatti
3) Fluvoksamin maleat
4) Fluvoxamina
5) (E)-5-Methoxy-4'-trifluoromethylvalerophenone-O-2-aminoethyloxmine maleate
6) CAS 54739-18-3 (Fluvoxamine)
7) CAS 61718-82-9 (Fluvoxamine maleate)

Available Forms Sources

1) Fluvoxamine is available in the United States as 25 mg, 50 mg, and 100 mg immediate-release tablets, and 100 mg and 150 mg extended-release capsules (Prod Info fluvoxamine maleate oral tablets, 2009; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).

1) The extended-release formulation of fluvoxamine is indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder. It is also indicated for social anxiety disorder, also known as social phobia (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
2) The immediate-release formulation of fluvoxamine is indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (Prod Info fluvoxamine maleate oral tablets, 2009).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Fluvoxamine is used to treat depression, obsessive-compulsive disorders, panic disorders, and as adjunctive treatment for migraine and chronic pain syndromes. Fluvoxamine has essentially no abuse potential.
B) PHARMACOLOGY: Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI).
C) TOXICOLOGY: The toxicity associated with fluvoxamine is likely due to an overabundance of serotonin activity after overdose, or use with other serotonergic agents.
D) EPIDEMIOLOGY: Fluvoxamine overdose is relatively rare compared with other more popular SSRIs. Toxicity is usually very mild, especially if no other substances are co-ingested.
E) WITH THERAPEUTIC USE

1) Sexual dysfunction has been reported at therapeutic doses. Nausea, vomiting, and abdominal pain may occur at low doses. Therapeutic dosing may decrease heart rate, but not to clinically significant bradycardia. Rarely, patients may exhibit increased suicidality after initiating fluvoxamine therapy. Drug discontinuation syndrome may rarely occur with cessation of therapy. Symptoms may include dizziness, lethargy, paresthesias, nausea, vivid dreams, irritability, and depressed mood.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE: The most common toxicity in overdose is CNS depression. Symptoms of mild toxicity include drowsiness, tremor, nausea, vomiting, abdominal pain, bradycardia, and anticholinergic effects.
2) SEVERE: Seizures have been reported following overdoses equal to or greater than 1500 mg; however, this is very rare. One case of prolonged CNS depression after ingestion of 3 g of fluvoxamine has been reported. Serotonin syndrome (altered mental status, neuromuscular rigidity, and autonomic instability) rarely occurs with single substance ingestions of fluvoxamine; however, there is increased risk for developing potentially life-threatening serotonin syndrome when multiple serotonergic drugs are ingested.

0.2.20)

A) Fluvoxamine is classified as FDA pregnancy category C. Although human and animal studies of fluvoxamine use during pregnancy did not reveal substantial teratogenicity, nonteratogenic effects (pulmonary hypertension of the newborn (PPHN) and clinical findings consistent with serotonin syndrome) and increased special or intensive unit care of the infant were demonstrated following maternal use of fluvoxamine during the third trimester of pregnancy. An increased risk for social-behavioral abnormalities at 2 to 6 years of age was reported in children exposed to SSRIs or serotonin–norepinephrine reuptake inhibitors (SNRIs) in utero who developed neonatal abstinence syndrome (NAS) at birth. Fluvoxamine is excreted in human breast milk and has the potential for serious adverse effects in the nursing infant. Fertility was impaired in male and female rats treated with fluvoxamine before and during mating.

0.2.21)

A) At the time of this review, the manufacturer does not report any carcinogenic potential of fluvoxamine in humans.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Supportive care is sufficient in nearly all patients. Antiemetics should be given if nausea and vomiting occur. Bradycardia does not usually require intervention; however, cardiac monitoring should be instigated for bradycardic patients. Investigation should be undertaken to assess for possibility of co-ingestants that may complicate the clinical course.

B) MANAGEMENT OF SEVERE TOXICITY

1) Supportive care remains the mainstay of treatment. Seizures should be managed with benzodiazepines. Patients with co-ingestants causing respiratory depression or loss of airway reflexes should be intubated. Hypotension is rare but should be treated with IV fluids and vasopressors if necessary. Patients with severe toxicity have likely ingested other substances. In serotonin syndrome, muscular rigidity is at least partially responsible for hyperthermia and death. External cooling and aggressive use of benzodiazepines should be used to limit morbidity and mortality. In severe serotonin syndrome, neuromuscular blockade with intubation may be required to relieve rigidity. Cyproheptadine is an antihistamine with nonspecific serotonin receptor antagonism that has been used successfully in mild to moderate serotonin toxicity.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital decontamination is generally not indicated.
2) HOSPITAL: Consider activated charcoal for recent, large (greater than 1000 mg) ingestions. Orogastric lavage and whole bowel irrigation are not indicated in fluvoxamine overdose. Each method carries some risk and fluvoxamine overdoses are usually not life threatening.

D) AIRWAY MANAGEMENT

1) Airway management is unlikely to be necessary unless co-ingestants that cause respiratory depression are present. Patients with CNS depression and normal respiration and airway reflexes should not be intubated prophylactically.

E) ANTIDOTE

1) None

F) HYPOTENSIVE EPISODE

1) Administer IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.

G) SEIZURE

1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.

H) SEROTONIN SYNDROME

1) Sedate with benzodiazepines. Consider cyproheptadine in patients with more severe manifestations who are able to take oral medications: ADULT dose 12 mg orally initially, then 2 mg every 2 hours if manifestations persist (maximum 32 mg in 24 hours), maintenance dose 8 mg every 6 hours. CHILDREN: 0.25 mg/kg/day divided every 6 hours, maximum 12 mg/day. If hyperthermic, control agitation/rigidity (benzodiazepines) and initiate external cooling measures (undress patient, cover with wet sheet and direct fan at skin). In severe cases, neuromuscular blockade (non-depolarizing agents) may be necessary.

I) HYPERSENSITIVITY REACTION

1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.

J) ENHANCED ELIMINATION

1) Due to the large volume of distribution of fluvoxamine, methods to enhance elimination are not useful.

K) PATIENT DISPOSITION

1) HOME CRITERIA: Children and adults with mild symptoms (eg, vomiting, mydriasis, diaphoresis, mild somnolence) following an inadvertent ingestion of up to 250 mg fluvoxamine can be managed at home with instructions to call the poison center back, if symptoms develop. For patients already on fluvoxamine, those with ingestions of up to 5 times their own single therapeutic dose can be observed at home with instructions to call the poison center back, if symptoms develop.
2) OBSERVATION CRITERIA: Any patient with an intentional ingestion or who develops more than mild symptoms should be sent to a healthcare facility for evaluation and treatment. For fluvoxamine naive patients with ingestions of more than 250 mg and for patients on chronic fluvoxamine therapy with an ingestion of more than 5 times that patient's single therapeutic dose, prompt referral to a healthcare facility is necessary for evaluation and treatment. Patients should be observed for 8 hours. For ingestion of extended-release formulations, observation may be warranted for up to 10 to 18 hours.
3) ADMISSION CRITERIA: Patients with severe CNS depression, signs and symptoms of serotonin syndrome, and/or co-ingestions of other more toxic symptoms may require admission. In general, patients will be asymptomatic within 24 to 48 hours.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for patients with severe toxicity or unclear diagnosis. Patients with signs and symptoms of serotonin syndrome warrant aggressive management, ICU admission, and toxicology consultation.

L) PITFALLS

1) The primary pitfall is failure to recognize co-ingestion of more toxic substances or attributing symptoms of a more serious illness to fluvoxamine ingestion. Onset of toxicity may be delayed an duration prolonged after overdose of sustained release formulations.

M) PHARMACOKINETICS

1) Peak plasma concentrations are reached in 4 to 12 hours with extended release enteric coated tablets or 2 to 8 hours with capsules or film-coated tablets. Fluvoxamine undergoes extensive hepatic metabolism with renal elimination of metabolites. The volume of distribution is 25 L/kg and the half-life is about 16 hours.

N) TOXICOKINETICS

1) Alterations in absorption, half-life, protein binding, metabolism, onset, and duration of action after overdose are not clear. Patients are generally symptom free within 24 to 48 hours after overdose.

O) PREDISPOSING CONDITIONS

1) Fluvoxamine pharmacokinetics are not substantially altered by increased age or renal impairment. Its elimination is prolonged in patients with hepatic cirrhosis. Fluvoxamine inhibits CYP1A2. Ingestion with another agent that increases serotonin can cause serotonin syndrome.

P) DIFFERENTIAL DIAGNOSIS

1) Other selective serotonin reuptake inhibitor (SSRI) overdose, tricyclic antidepressant (TCA) overdose, anticholinergic overdose

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) WITH POISONING/EXPOSURE

1) Mild hyperpyrexia was seen in an adult who ingested 2500 mg of fluvoxamine together with 6 capsules of brompheniramine and flurazepam (Crome & Ali, 1986).

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) MIOSIS has been noted in patients taking this agent therapeutically (Wilson et al, 1983).

B) WITH POISONING/EXPOSURE

1) MYDRIASIS has been reported in overdose (Garnier et al, 1993).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Orthostatic hypotension has been reported with therapeutic administration in obsessive compulsive patients. It improved later in individual therapy (Price et al, 1987).

2) WITH POISONING/EXPOSURE

a) Mild hypotension has been reported with overdose (Garnier et al, 1993).

B) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Mild hypertension was seen in an adult who ingested 2500 mg of fluvoxamine together with 6 capsules of brompheniramine and flurazepam (Crome & Ali, 1986).

C) ELECTROCARDIOGRAM ABNORMAL

1) WITH THERAPEUTIC USE

a) Electrocardiographic changes have been minor when given therapeutically (Robinson & Doogan, 1982).
b) In a analysis of ECG data from several authors, fluvoxamine caused slight increases in the R-R, QT, and QTc intervals (Guelfi et al, 1983; DeWilde & Doogan, 1982; DeWilde et al, 1983; Benfield & Ward, 1986). T-wave configurations like those seen after tricyclic antidepressant administration were not seen (Roos, 1983).

2) WITH POISONING/EXPOSURE

a) Electrocardiogram (ECG) abnormalities have been observed with fluvoxamine overdose and include heart arrest, QT interval prolongation, first degree atrioventricular block, bundle branch block, and junctional rhythm (Prod Info fluvoxamine maleate oral tablets, 2012).
b) CASE REPORTS

1) A 25-year-old woman developed status epilepticus and a pulseless electrical activity approximately 16 hours after ingesting 9.6 g of fluvoxamine. Following intensive supportive therapy, she recovered completely and was discharged home after 72 hours (Wood et al, 2007).
2) Sinus tachycardia with generalized non-specific T-wave flattening and T-wave inversion occurred in a 21-year-old woman who ingested 6000 mg of fluvoxamine (Deshpande, 2002).
3) A 32-year-old woman developed QT segment lengthening, T wave alterations, and first degree right branch block after ingesting approximately 1500 mg fluvoxamine, 1600 mg pipamperone, and 50 mg lorazepam in an apparent suicide attempt. The ECG abnormalities resolved the following day (Gallerani et al, 1998).
4) A 63-year-old who took 1,500 mg and a 74-year-old who took 3 g both had normal electrocardiograms (Lam et al, 1988; Banerjee, 1988).

D) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) In a survey of 228 cases, sinus bradycardia was the most common sign of cardiac toxicity (Azoyan et al, 1990).
b) CASE REPORT: One case describes a 59-year-old woman who ingested 2 g fluvoxamine, 200 mg buspirone, and 300 mg flurazepam in a suicide attempt. Bradycardia was noted on admission to the ED with ECG readings showing sinus bradycardia which lasted nearly 8 days following the overdose. Blood pressure remained normal throughout her hospital stay (Langlois & Paquette, 1994).
c) Bradycardia not requiring treatment has been reported after ingestion of less than 1000 mg (Garnier et al, 1993).
d) CASE REPORT: A 58-year-old woman developed severe sinus bradycardia and complained of severe fatigue several hours after ingesting 5.5 g of fluvoxamine in an apparent suicide attempt. The patient recovered following supportive care (Amital et al, 1994).

E) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Sinus tachycardia has been reported (Deshpande, 2002; Garnier et al, 1993).
b) CASE REPORT: Tachycardia developed in an adult who ingested 2500 mg of fluvoxamine together with 6 capsules of brompheniramine and flurazepam (Crome & Ali, 1986).

F) VENTRICULAR ARRHYTHMIA

1) WITH THERAPEUTIC USE

a) PVCs not requiring therapy have been occasionally reported (Garnier et al, 1993).

3.5.3)

A) ANIMAL STUDIES

1) DYSRHYTHMIA

a) ANIMAL STUDIES: When studied in rabbits, dysrhythmias were infrequently seen. ECG disturbances were seen only at doses nearing lethality (Wouthers & Deiman, 1983).

Respiratory

3.6.2)

A) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Respiratory depression may be seen in conjunction with coma. Cases where respiratory support was required also involved benzodiazepines in the overdose (Banerjee, 1988; Lam et al, 1988).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH THERAPEUTIC USE

a) Somnolence was noted in 26% of patients taking fluvoxamine therapeutically (Benfield & Ward, 1986).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Coma developed in a 74-year-old who ingested 3 g in combination with 250 mg of temazepam (Banerjee, 1988).
b) CASE REPORT: Coma, necessitating respiratory assistance, was also noted in a 63-year-old who ingested 1,500 mg of fluvoxamine and 40 mg of flunitrazepam (Lam et al, 1988).
c) Mild drowsiness has also been reported after overdose (Garnier et al, 1993).
d) CASE REPORT: A 32-year-old woman presented to the ED in a comatose state (Glasgow Coma Scale of 7) 5 hours after ingesting 1500 mg fluvoxamine, 1600 mg pipamperone, and 50 mg lorazepam in an apparent suicide attempt. The patient recovered following gastric lavage and intravenous infusion of flumazenil (Gallerani et al, 1998).

B) HEADACHE

1) WITH THERAPEUTIC USE

a) Headache was noted in 22% of patients taking this drug therapeutically (Benfield & Ward, 1986).

C) PSYCHOMOTOR AGITATION

1) WITH THERAPEUTIC USE

a) Agitation was noted in 16% of patients taking this drug therapeutically (Benfield & Ward, 1986).
b) CASE REPORT: Severe agitation has been reported in an 11-year-old boy following the ingestion of one therapeutic (50 mg) fluvoxamine tablet (Gill et al, 1999).
c) CASE REPORT: A 68-year-old man experienced severe agitation and restlessness within one week of beginning fluvoxamine therapy, 50 mg daily. The akathisia began to subside gradually following discontinuation of the fluvoxamine and administration of diazepam (Chong & Cheong, 1999).

2) WITH POISONING/EXPOSURE

a) Agitation was seen in an adult who ingested 2500 mg of fluvoxamine together with 6 capsules of brompheniramine and flurazepam (Crome & Ali, 1986).

D) SEIZURE

1) WITH THERAPEUTIC USE

a) Seizures were reported in 0.2% of patients treated with fluvoxamine during premarketing studies (Prod Info fluvoxamine maleate oral tablets, 2012).
b) CASE REPORT: A 49-year-old man, with a past medical history of seizures and who had been seizure-free for 10 years with anticonvulsant therapy, experienced a generalized seizure three days after beginning fluvoxamine therapy, 150 mg at bedtime. Following an increase in dosage of the anticonvulsant therapy, the patient did not experience any more seizures (Kim et al, 2000).

2) WITH POISONING/EXPOSURE

a) One case reports a series of 221 acute overdoses with fluvoxamine. In 77% of the cases other agents, primarily benzodiazepines, neuroleptics, other antidepressants and alcohol were also ingested. The acute toxicity that could be attributed to fluvoxamine alone was rarely severe. Seizures occurred in a few cases after high doses (generally greater than 1500 mg) (Garnier et al, 1993)
b) CASE REPORT: Generalized tonic-clonic seizures and hypertonicity with upgoing plantar reflexes occurred in a 21-year-old woman approximately 30 minutes after ingesting 6000 mg of fluvoxamine. The patient recovered with supportive care (Deshpande, 2002).
c) CASE REPORT: A 25-year-old woman presented with drowsiness 12 hours after ingesting 9.6 g of fluvoxamine. Approximately 4 hours later, she developed generalized tonic-clonic seizures, unresponsive to lorazepam and midazolam. During status epilepticus, she developed a pulseless electrical activity, requiring three cycles of cardiopulmonary resuscitation. She continued to have seizures, requiring several anticonvulsant treatments (thiopentone, phenytoin, and phenobarbitone). She recovered gradually and was discharged home after 72 hours without further sequela (Wood et al, 2007).

E) HALLUCINATIONS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Both tactile and visual hallucinations were seen in an adult who ingested 2500 mg of fluvoxamine together with 6 capsules of brompheniramine and flurazepam (Crome & Ali, 1986).

F) DIZZINESS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Intense dizziness, mild psychomotor impairment, ataxia, and slowed but coherent speech developed in a 59-year-old woman after intentional ingestion of 2000 mg fluvoxamine, 200 mg buspirone, and 300 mg flurazepam (Langlois & Paqueete, 1994).

G) TREMOR

1) WITH POISONING/EXPOSURE

a) Tremor has been reported rarely after overdose (Garnier et al, 1993).

H) SEROTONIN SYNDROME

1) WITH THERAPEUTIC USE

a) Serotonin syndrome (altered mental status, neuromuscular rigidity, and autonomic instability) rarely occurs with single substance ingestions of fluvoxamine; however, there is increased risk for developing potentially life-threatening serotonin syndrome when multiple serotonergic drugs are ingested (Prod Info fluvoxamine maleate oral tablets, 2012).
b) CASE REPORT: Serotonin syndrome has been reported in an 11-year-old boy following the ingestion of one therapeutic (50 mg) fluvoxamine tablet (Gill et al, 1999).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea and vomiting are common early in fluvoxamine therapy; up to 37% of individuals experience this side effect (Benfield & Ward, 1986).

B) APTYALISM

1) WITH THERAPEUTIC USE

a) Dry mouth occurred in about 3.7% to 26% of patients who were on fluvoxamine therapy (Benfield & Ward, 1986; Martin et al, 1987).

2) WITH POISONING/EXPOSURE

a) Dry mouth has been reported after overdose (Garnier et al, 1993).

C) CONSTIPATION

1) WITH THERAPEUTIC USE

a) Constipation was reported in 18% of patients on therapy (Benfield & Ward, 1986).

D) LOSS OF APPETITE

1) WITH THERAPEUTIC USE

a) Anorexia developed in 15% of patients on therapy (Benfield & Ward, 1986).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH THERAPEUTIC USE

a) Reports of liver toxicity are rare therapeutically. One man reported a three fold increase in gamma glutamyl transferase over baseline and an enlarged liver after 3 weeks of fluvoxamine 100 mg twice daily (Green, 1988).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Elevated ASAT, ALAT, GGT, and bilirubin were reported in a 63-year-old who ingested 1,500 mg (Lam et al, 1988).
b) Elevated aminotransferases developed in one patient out of 69 who ingested overdoses of fluvoxamine alone (Garnier et al, 1993).
c) 15 of 228 cases in one study had elevated enzymes, however, a direct, causal relationship could not be proven (Azoyan et al, 1990).

Endocrine

3.16.2)

A) HYPOGLYCEMIA

1) WITH POISONING/EXPOSURE

a) Mild hypoglycemia developed in one of 69 patients with overdose of fluvoxamine alone (Garnier et al, 1993).

Reproductive

3.20.1)

3.20.2)

A) LACK OF EFFECT

1) CASE REPORT: A 33-year-old woman was treated with fluvoxamine 200 mg/day and quetiapine 400 mg/day, during her second pregnancy, resulting in an uneventful pregnancy and the birth of a healthy female infant. The patient gained 9 kg with no symptoms of psychiatric instability. Routine biochemical tests were within the normal range and 5 echographic reports found no fetal abnormalities. The presence of an intrauterine myoma led to an elective caesarean-section. A healthy female infant weighing 2600 g and measuring 49 cm in length had Apgar scores of 9 and 10 at 1 minute and 5 minutes, respectively (Gentile, 2006).
2) One small human study that used fluvoxamine found no increase in malformations between infants exposed to the drug and those with no exposure (Kulin et al, 1998). Another larger, population-based study found no increased risk of malformations, but the exposed infants were more likely to require treatment in a special or intensive care unit (Malm et al, 2005).

B) ANIMAL STUDIES

1) RATS: Pregnant rats treated with oral fluvoxamine at doses of 60, 120, or 240 mg/kg throughout the pregnancy delivered offspring with developmental toxicity including embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) at doses of 120 mg/kg or greater and decreased body weight at doses of 240 mg/kg. The developmental toxicity no-effect dose was 60 mg/kg (2 times the maximum recommended human dose (MRHD)). In female rats treated with fluvoxamine at doses between 5 and 60 mg/kg, pup mortality at birth increased at doses of 80 mg/kg or greater and pup body weight and survival decreased at all doses with a low effect dose about 0.1 times the MRHD (Prod Info LUVOX(R) oral tablets, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
2) RABBITS: In a study of pregnant rabbits, no embryofetal adverse effects were observed at oral doses of fluvoxamine up to 40 mg/kg (2 times the MRHD) (Prod Info LUVOX(R) oral tablets, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).

3.20.3)

A) PREGNANCY CATEGORY

1) Fluvoxamine is classified as FDA pregnancy category C. (Prod Info LUVOX(R) oral tablets, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
2) In a prospective longitudinal study of 201 women with a history of major depression and no signs of depression at the beginning of pregnancy, there was a greater likelihood of relapse of major depression in those who discontinued antidepressant drugs during pregnancy compared with those who continued antidepressant drugs throughout the pregnancy (Prod Info LUVOX(R) oral tablets, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).

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) LONG TERM NEURODEVELOPMENT

1) In a prospective, single-blind, cohort study, full-term infants who developed neonatal abstinence syndrome (NAS) at birth had similar cognitive abilities compared with full term infants without NAS at birth when reevaluated at 2 to 6 years of age. However, infants with NAS at birth were at an increased risk for social-behavioral abnormalities at 2 to 6 years of age. The study was designed to assess the long-term neurodevelopment of children exposed in utero to fluoxetine, paroxetine, citalopram, sertraline, fluvoxamine, or venlafaxine. Children with NAS at birth (n=30; Finnegan score of 4 or greater) were compared to children without NAS (n=52; Finnegan score 0 to 3); both groups were similar in mean cognitive ability (106.9 +/- 14 versus 100.5 +/- 14.6, respectively; p=0.12) and developmental scores (98.9 +/- 11.4 versus 95.7 +/- 9.9, respectively; p=0.21). Cognitive ability was based on scores from the Wechsler Preschool and Primary Scale of Intelligence II, the Stanford-Binet Intelligence Scales, or the Bayley Scale of Infant Development II. The NAS infants had an increased risk of social-behavior abnormalities (odds ratio (OR) 3.03, 95% CI, 1.07 to 8.6, p=0.04) based on the Denver Developmental Screening Test II (DDST-II) and NAS after birth was associated with advanced maternal age (OR 1.12, 95% CI, 1 to 1.25, p=0.04). In addition, there was a trend towards small head circumference in the NAS group when compared with the children without NAS (n=6 (20%) versus n=3 (6%), respectively; p=0.068) (Klinger et al, 2011).

D) SPONTANEOUS ABORTION

1) A nested case-controlled study showed that fluvoxamine, sertraline, fluoxetine, citalopram, or combined use of 2 or more SSRIs during pregnancy did not correspond with a significantly increased risk of spontaneous abortion. However, paroxetine or venlafaxine use alone did increase the spontaneous abortion risk. Data collected from the Quebec Pregnancy Registry between January 1998 and December 2003 on women who filled at least 1 antidepressant prescription during pregnancy and had a clinically detected spontaneous abortion by the twentieth week of gestation (n=284) showed an increased risk of spontaneous abortion (adjusted odds ratio (OR), 1.68; 95% confidence interval (CI), 1.38 to 2.06) when compared with randomly selected registry controls (4 matched controls per case) without antidepressant use. Tracked antidepressant categories included SSRIs, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, combined use of 2 or more antidepressant classes, or others. Paroxetine use (adjusted OR 1.75; 95% CI, 1.31 to 2.34) or venlafaxine use (adjusted OR 2.11; 95% CI, 1.34 to 3.3) alone were independently associated with a higher risk of spontaneous abortion. The highest daily doses of paroxetine or venlafaxine during pregnancy were associated with the greatest spontaneous abortion risk; of the women taking paroxetine (n=84) or venlafaxine (n=33) who spontaneously aborted, an adjusted analysis showed 25.5% averaged daily doses of more than 25 mg of paroxetine and 50% averaged daily doses greater than 150 mg of venlafaxine. (Nakhai-Pour et al, 2010).

E) QT PROLONGATION

1) A study of prospectively collected data suggests antenatal use of selective serotonin-reuptake inhibitor (SSRI) antidepressants is associated with QTc interval prolongation in exposed neonates. Between January 2000 and December 2005, researchers compared 52 neonates exposed to SSRI antidepressants (paroxetine (n=25), citalopram (n=13), fluoxetine (n=12), fluvoxamine (n=1), and venlafaxine (n=1)) in the immediate antenatal period to 52 matched neonates with no exposure. Prolonged QTc is defined as an interval of greater than 460 milliseconds (msec) (the widely used upper limit cited by authorities in both pediatric cardiology and neonatology). A pediatric cardiologist blinded to drug exposure, interpreted all electrocardiograms (ECGs) using standard statistical analyses. ECG recordings revealed markedly prolonged mean QTc intervals in exposed neonates compared to unexposed neonates (mean; 409 +/- 42 msec versus 392 +/- 29 msec, p=0.02). The mean uncorrected QT interval was 7.5% longer among exposed neonates (mean; 280 +/- 31 msec versus 261 +/- 25 msec, p less than 0.001). Ten percent (n=5) of exposed neonates had a notable increase in QTc interval prolongation (greater than 460 msec) compared to none of the unexposed neonates. The longest QTc interval observed was 543 msec (Dubnov-Raz et al, 2008).

F) SEROTONERGIC EFFECTS

1) Neonates exposed to fluvoxamine and other SSRIs late in the third trimester have developed complications, including respiratory distress, seizures, vomiting, tremor, and irritability that were consistent with either SSRI toxicity or a possible drug discontinuation syndrome. In some cases, clinical findings were consistent with serotonin syndrome (Prod Info LUVOX(R) oral tablets, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
2) An increased risk for central nervous system serotonergic symptoms was observed during the first four days of life in infants of mothers taking SSRIs during the third trimester of pregnancy. In a controlled, prospective study, women taking 20 to 40 mg/day of either citalopram (n=10) or fluoxetine (n=10) while pregnant where compared with a control group (n=20). Exposure to SSRI therapy ranged from 7 to 41 weeks. Newborns in the SSRI group had a lower Apgar score at 15 minutes compared with the control group (8.8 vs 9.4; p=0.02). The only significant difference observed in the vital signs of the newborns was a higher heart rate in the SSRI group at two weeks compared with the controls (mean, 153 bpm vs 141 bpm; p=0.049). Serotonergic symptom scores in the first 4 days after birth were significantly higher in the SSRI group than in the control group (total score, 121 vs 30, respectively; p=0.008). Tremor, restlessness, and rigidity were the most prominent symptoms. Myoclonus was reported in one infant exposed to fluoxetine. Significantly lower cord blood 5-hydroxyindoleacetic acid (5-HIAA) concentrations were seen in the SSRI-exposed infants compared with the control group (mean, 63 mmol/L vs 77 mmol/L; p=0.02). Additionally, a significant inverse correlation was observed between the serotonergic symptom score and the umbilical vein 5-HIAA concentrations in the SSRI-exposed newborns, but not in the control group (p=0.007). Although not statistically significant, mean umbilical cord serum prolactin concentrations were 29% lower in SSRI-exposed infants than in control infants at the time of birth (Laine et al, 2003).

G) PULMONARY HYPERTENSION

1) In a case control study of women who delivered infants with pulmonary hypertension of the newborn (PPHN; n=377) and women who delivered healthy infants (n=836), the risk for developing PPHN was approximately six-fold higher in infants exposed to SSRIs after week 20 of gestation compared with infants not exposed to SSRIs during gestation. This study demonstrates a potential increased risk of PPHN, associated with considerable neonatal morbidity and mortality, in infants exposed to SSRIs later in the pregnancy. In the general population, PPHN occurs in 1 to 2 per 1000 live births (Prod Info LUVOX(R) oral tablets, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).

H) LACK OF EFFECT

1) A population-based study of 1782 pregnant women exposed to SSRIs found no increased risk of adverse perinatal outcome except for treatment in the neonatal intensive or special care unit, particularly with third trimester exposure. Using 1996-2001 data derived from a government project involving 4 birth or medication registries in Finland, women who had at least one purchase (a 3-month supply) of an SSRI during the period of one month before pregnancy and the day pregnancy ended were compared with 1782 controls with no reimbursed drug purchases during the same peripartum period. The mean age of both cohorts was 30 years (+/- 7). There were more than twice as many smokers and six times as many pregnancies induced by artificial reproductive techniques in the SSRI group compared to controls (p < 0.001), and mean length of gestation and birth weight were lower (p < 0.001) in the SSRI group. Malformations, however, were not more common in the SSRI group (p = 0.4). Purchases of SSRIs (citalopram, fluoxetine, paroxetine, sertraline and fluvoxamine) were more common in the first trimester than later in pregnancy, with 65 women purchasing fluvoxamine during the first trimester, 23 during the second trimester, 27 during the third, and 10 throughout pregnancy. When compared with first trimester exposure, treatment in a special or intensive care unit was more common for the infants exposed during the third trimester (11.2% and 15.7%, respectively; p = 0.009). Even after adjusting for confounding variables, this difference remained statistically significant (OR 1.6; 95% CI 1.1-2.2) (Malm et al, 2005).

3.20.4)

A) LACK OF EFFECT

1) The American Academy of Pediatrics considers antidepressants to be drugs worthy of concern in the nursing infant, in particularly during long-term use (Anon, 2001). The long-term effects of exposure to SSRIs via breast milk on the cognitive development of the infant have not been determined (Kristensen et al, 2002).
2) CASE REPORT: A 33-year-old woman was treated with fluvoxamine 200 mg/day and quetiapine 400 mg/day, during her second pregnancy, resulting in an uneventful pregnancy and the birth of a healthy female infant weighing 2600 g and measuring 49 cm in length with Apgar scores of 9 and 10 at 1 minute and 5 minutes, respectively. The patient chose to breastfeed; however, formula was required to supplement her breast milk due to insufficient milk production. In the 3 months that the infant received breast milk supplemented with formula, no adverse effects were detected and the infant continues to develop normally (Gentile, 2006).
3) In a study of 2 mother-infant pairs, there were no adverse effects from fluvoxamine found in either nursing infant. The infants were 26 months and 0.75 months of age at the time of the study, which involved collecting venous blood samples and breast milk over a 24 hour dosing interval. Assuming a milk intake for both infants of 0.15 L/kg/day, the infant dose calculated as a percentage of the weight adjusted maternal dose were 1.38% (26-month-old infant) and 0.8% (0.75-month-old infant). The milk to plasma ratios were 1.34 and 1.21, respectively. Fluvoxamine was not detected in the plasma of either infant. The 26-month-old infant had a Denver developmental assessment with a quotient of 115, indicating that the infant achieved the anticipated milestones. The 0.75-month-old infant was too young to have a meaningful Denver assessment, so a detailed pediatric examination was performed and found no abnormalities. Both mothers reported that the health and progress of their infants was satisfactory (Kristensen et al, 2002).

3.20.5)

A) ANIMAL STUDIES

1) Fertility studies in male and female rats treated with fluvoxamine (60, 120, or 240 mg/kg) before and during gestation demonstrated effects of impaired fertility at oral doses of 120 mg/kg or greater, including increased latency to mating, decreased sperm count, reduced epididymal weight and decreased pregnancy rate. At the highest dose, there was a decrease in the numbers of implantations and embryos. The no effect dose for fertility impairment was 60 mg/kg (approximately 2 times the maximum recommended human dose based on surface area) (Prod Info LUVOX(R) oral tablets, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).

Carcinogenicity

3.21.2)

A) At the time of this review, the manufacturer does not report any carcinogenic potential of fluvoxamine in humans.

3.21.3)

A) LACK OF INFORMATION

1) At the time of this review, the manufacturer does not report any carcinogenic potential of fluvoxamine in humans.

3.21.4)

A) LACK OF EFFECT

1) Fluvoxamine was not carcinogenic in rats treated with doses between 160 mg/kg/day and 240 mg/kg/day for 30 months or in hamsters treated with doses between 135 mg/kg/day to 240 mg/kg/day for up to 26 months. The maximum dose of 240 mg/kg is approximately 6 times the maximum recommended human daily dose on a mg/m(2) basis (Prod Info fluvoxamine maleate oral tablets, 2011).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs (including temperature) and mental status. Evaluate for clinical evidence or serotonin syndrome (hyperreflexia, clonus, myoclonus, tremors etc.).
B) Monitor ECG.
C) Obtain basic metabolic panel, salicylate and acetaminophen concentrations after deliberate overdose .
D) Direct laboratory analysis towards ruling out more serious ingestions and conditions.
E) Fluvoxamine concentrations are generally not available and do not correlate with symptoms.

4.1.2)

A) Obtain salicylate and acetaminophen levels.
B) Direct laboratory analysis towards ruling out more serious ingestions and conditions.
C) Fluvoxamine concentrations are generally not available and do not correlate with symptoms.
D) BLOOD/SERUM CHEMISTRY

1) GAMMA GLUTAMYL TRANSFERASE: Increases of more than 3-fold over baseline were seen following 3 weeks of fluvoxamine 100 mg twice daily (Green, 1988). The levels dropped to near normal 5 weeks after stopping the therapy. Other liver enzymes have been elevated after overdose, and should be monitored (Lam et al, 1988).
2) SERUM MELATONIN: Increases were noted in healthy male volunteers who took 150 mg of fluvoxamine at night (Demisch et al, 1986).

4.1.4)

A) OTHER

1) ECG

a) Monitor ECG.

Methods

1) Fluvoxamine has been determined in plasma by the use of high performance liquid chromatography (DeJong, 1980) and electron capture gas chromatography (Hurst, 1981).
2) A liquid chromatography/ultraviolet detection method has been used to assay fluvoxamine levels in serum and in breast milk (Arnold et al, 2000).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with severe CNS depression, signs and symptoms of serotonin syndrome, and/or co-ingestions of other more toxic symptoms may require admission. In general, patients will be asymptomatic within 24 to 48 hours (Garnier et al, 1993a; Henry, 1991).

6.3.1.2) HOME CRITERIA/ORAL

A) Children and adults with mild symptoms (eg, vomiting, mydriasis, diaphoresis, mild somnolence) following an inadvertent ingestion of up to 250 mg fluvoxamine can be managed at home with instructions to call the poison center back, if symptoms develop. For patients already on fluvoxamine, those with ingestions of up to 5 times their own single therapeutic dose can be observed at home with instructions to call the poison center back, if symptoms develop (Nelson et al, 2007).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for patients with severe toxicity or unclear diagnosis. Patients with signs and symptoms of serotonin syndrome warrant aggressive management, ICU admission, and toxicology consultation.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Any patient with an intentional ingestion or who develops more than mild symptoms should be sent to a healthcare facility for evaluation and treatment. For fluvoxamine naive patients with ingestions of more than 250 mg and for patients on chronic fluvoxamine therapy with an ingestion of more than 5 times that patient's single therapeutic dose, prompt referral to a healthcare facility is necessary for evaluation and treatment. Patients should be observed for 8 hours (Nelson et al, 2007). For ingestion of extended-release formulations, observation may be warranted for up to 10 to 18 hours.

Monitoring

Oral Exposure

6.5.1)

A) Prehospital decontamination is generally not indicated.

6.5.2)

A) Consider activated charcoal for recent, large (greater than 1000 mg) ingestions. Orogastric lavage and whole bowel irrigation are not indicated in fluvoxamine overdose. Each method carries some risk and fluvoxamine overdoses are usually not life threatening.
B) 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)

A) MONITORING OF PATIENT

1) Monitor vital signs (including temperature) and mental status.
2) Monitor ECG.
3) Obtain salicylate and acetaminophen levels.
4) Direct laboratory analysis towards ruling out more serious ingestions and conditions.
5) Fluvoxamine concentrations are generally not available and do not correlate with symptoms.

B) FLUID/ELECTROLYTE BALANCE REGULATION

1) Although vomiting has not been extensive in overdose to date, patients should be monitored for fluid and electrolyte loss, and appropriate replacement therapy instituted when necessary.

C) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) 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).

D) 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).

E) 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).

F) HYPERSENSITIVITY REACTION

1) SUMMARY

a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.

2) BRONCHOSPASM

a) ALBUTEROL

1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

3) CORTICOSTEROIDS

a) Consider systemic corticosteroids in patients with significant bronchospasm.
b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).

4) MILD CASES

a) DIPHENHYDRAMINE

1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).

5) MODERATE CASES

a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).

6) SEVERE CASES

a) EPINEPHRINE

1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).

7) AIRWAY MANAGEMENT

a) OXYGEN: 5 to 10 liters/minute via high flow mask.
b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

8) MONITORING

a) CARDIAC MONITOR: All complicated cases.
b) IV ACCESS: Routine in all complicated cases.

9) HYPOTENSION

a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.

1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).

10) H1 and H2 ANTIHISTAMINES

a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).

1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).

b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).

11) DYSRHYTHMIAS

a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.

12) OTHER THERAPIES

a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

1) Due to the large volume of distribution of fluvoxamine, methods to enhance elimination are NOT useful.

Abstracts

Case Reports

1) ADULT

a) A 74-year-old ingested 3 g of fluvoxamine and 250 mg of temazepam. The patient was lavaged in the emergency department.

1) She was comatose, afebrile, with a heart rate of 70 beats per minute, a respiratory rate of 20, and a blood pressure of 80/50 mmHg. She had no gag reflex, and was unresponsive to pain.
2) The electrocardiogram was normal. She was treated with supportive measures and within 24 hours her blood pressure had returned to normal (110/70 mmHg) (Banerjee, 1988).
3) This woman remained comatose for 5 days and improved on the 6th. The temazepam level peaked at over 1.8 mg/L within a few hours of ingestion. The fluvoxamine level peaked on day three at over 1.4 mg/L (Banerjee, 1988).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) OBSESSIVE COMPULSIVE DISORDER

1) IMMEDIATE RELEASE: 50 mg/day orally at bedtime; may increase by 50 mg increments every 4 to 7 days to a MAXIMUM dose of 300 mg/day. Total daily doses greater than 100 mg should be divided into 2 separate doses (Prod Info fluvoxamine maleate oral tablets, 2012).
2) EXTENDED-RELEASE: 100 mg/day orally at bedtime; may increase by 50 mg increments every week to a MAXIMUM dose of 300 mg/day (Prod Info LUVOX CR(R) oral extended release capsules, 2012).

B) SOCIAL PHOBIA

1) EXTENDED-RELEASE: 100 mg/day orally at bedtime; may increase by 50 mg increments every week to a MAXIMUM dose of 300 mg/day (Prod Info LUVOX CR(R) oral extended release capsules, 2012).

7.2.2)

A) OBSESSIVE COMPULSIVE DISORDER

1) AGES 8 TO 11 YEARS: IMMEDIATE RELEASE: 25 mg/day orally at bedtime; may increase by 25 mg increments every 4 to 7 days to a MAXIMUM dose of 200 mg/day (Prod Info fluvoxamine maleate oral tablets, 2012).
2) AGES 12 TO 17 YEARS: IMMEDIATE RELEASE: 25 mg/day orally at bedtime; may increase by 25 mg increments every 4 to 7 days to a MAXIMUM dosage of 300 mg/day (Prod Info fluvoxamine maleate oral tablets, 2012).

Minimum Lethal Exposure

1) Fluvoxamine toxicity appears to be highly variable. Greater than 45,000 patients have been exposed to Fluvoxamine in clinical trials and approximately 50,000,000 have been treated during worldwide marketing (as of 2005). Overdose has been reported in 539 cases resulting in 55 deaths. Of the 55 fatalities, 9 were attributed to ingestion of fluvoxamine alone. Ingestions as low as 1400 mg have resulted in death (Prod Info fluvoxamine maleate oral tablets, 2012).
2) In a review of 78 cases (all ages) of acute fluvoxamine ingestion, the lowest dose associated with death was 2500 mg (the age of the patient or the possibility of coingestants could not be determined) (Nelson et al, 2007).

Maximum Tolerated Exposure

1) Acute ingestion of up to 250 mg is not expected to result in significant toxicity. For patients already on fluvoxamine, those with ingestions of up to 5 times their own single therapeutic dose are not expected to develop significant toxicity (Nelson et al, 2007).
2) CASE SERIES

a) In a review of 78 cases (all ages) of acute fluvoxamine ingestion, 150 mg (age unknown) was the lowest dose associated with any toxicity; symptoms included abdominal pain and drowsiness (Nelson et al, 2007).
b) In a review of 221 reports of intentional fluvoxamine overdose from the Paris Poison Center and 78 cases from the International Drug Safety Department of Duphar BV, toxicity attributed to fluvoxamine alone was rarely severe and symptoms were universally mild with ingestions of less than 1000 mg. Symptoms observed included drowsiness, tremor, nausea, vomiting, abdominal pain, bradycardia, and/or anticholinergic effects (Garnier et al, 1993).

3) ADULT CASE REPORTS

a) An individual survived a fluvoxamine dose of 12,000 mg and fully recovered (Prod Info fluvoxamine maleate oral tablets, 2012).
b) A 25-year-old woman developed status epilepticus followed by pulseless electrical activity approximately 16 hours after ingesting 9.6 g of fluvoxamine (serum concentration on presentation, 1970 mcg/L; therapeutic range 160 to 220 mcg/L). Following intensive supportive therapy, she recovered completely and was discharged home after 72 hours (Wood et al, 2007).
c) A 21-year-old woman developed generalized tonic-clonic seizures and hypertonicity with upgoing plantar reflexes after ingesting 6000 mg of fluvoxamine, and recovered following supportive care (Deshpande, 2002).
d) A 58-year-old woman ingested 5.5 g fluvoxamine and developed severe sinus bradycardia. The patient recovered within 2 days following supportive care (Amital et al, 1994).
e) A 74-year-old who ingested 3 g of fluvoxamine and 250 mg of temazepam developed coma for 5 days (Banerjee, 1988).

1) A 4-year-old boy ingested an estimated 400 mg (20 mg/kg) fluvoxamine and developed hypotension, bradycardia, and seizure (Nelson et al, 2007).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORT: A 25-year-old woman developed status epilepticus and a pulseless electrical activity approximately 16 hours after ingesting 9.6 g of fluvoxamine (serum concentration on presentation, 1970 mcg/L; therapeutic range 160 to 220 mcg/L). Following intensive supportive therapy, she recovered completely and was discharged home after 72 hours (Wood et al, 2007).
2) CASE REPORT: A 32-year-old woman ingested approximately 1500 mg fluvoxamine. A serum drug screening determined that her fluvoxamine level was 1.5 mg/L (therapeutic range 0.03 to 0.09 mg/L) (Gallerani et al, 1998).

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (ORAL)MOUSE:

a) 1100 mg/kg (RTECS, 2001) (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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FLUVOXAMINE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

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Life Support

Clinical Effects

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Treatment Overview

Range Of Toxicity

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Heent

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Summary

Therapeutic Dose

Minimum Lethal Exposure

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Serum Plasma Blood Concentrations

Toxicity Information

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Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography