FLUOXETINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Fluoxetine hydrochloride
2) dl-N-methyl-3-phenyl-3-(alpha,alpha,alpha-trifluoro-p-tolyl) oxy)propylamine hydrochloride
3) Fontex
4) LILLY-103472
5) LILLY-110140
6) LY-110140
7) CAS 54910-89-3

1.2.1) MOLECULAR FORMULA
1) C17-H18-F3-N-O
2) C17H18F3NO-HCl

Available Forms Sources

1) Fluoxetine is available as 10 mg, 20 mg, and 40 mg capsules, 90 mg delayed-release capsules, 10 mg, 20 mg, and 60 mg tablets, 20 mg/5 mL oral solution, and 20 mg/5 mL oral syrup (Prod Info PROZAC(R) oral capsules, oral delayed release capsules, 2014; Prod Info SARAFEM(R) oral tablets, 2008).
2) Fluoxetine is also available in combination with olanzapine as 25 mg-3 mg, 25 mg-6 mg, 25 mg-12 mg, 50 mg-6 mg, 50 mg-12 mg capsules (Prod Info SYMBYAX(R) oral capsules, 2015).

1) Fluoxetine is used in the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder, depressive episodes associated with bipolar I disorder, and bulimia nervosa (Prod Info PROZAC(R) oral capsules, oral delayed release capsules, 2014). It is also used in the treatment of premenstrual dysphoric disorder (Prod Info SARAFEM(R) oral tablets, 2008).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and is used for depressive disorder, obsessive-compulsive disorder, panic attack, and bulimia nervosa.
B) PHARMACOLOGY: Fluoxetine and its active metabolite norfluoxetine inhibit reuptake of serotonin from the synaptic cleft, therefore increasing serotonergic neurotransmission.
C) TOXICOLOGY: Severe toxicity is not common, but may develop from excessive serotonergic effects, particularly when fluoxetine is ingested with another agent that increases CNS serotonin.
D) EPIDEMIOLOGY: Poisoning with fluoxetine and other SSRIs are common. Life threatening toxicity is rare, and patients usually recover without sequelae.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Somnolence, dizziness, insomnia, nervousness, headache, nausea, vomiting, and diarrhea are often reported. Hyponatremia, due to inappropriate secretion of antidiuretic hormone (SIADH), may be observed.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE POISONING: Somnolence, dizziness, nausea, and vomiting are common; QTc prolongation may occur even in therapeutic or mild overdose.
2) SEVERE POISONING: Significant CNS depression, seizures, and QTc prolongation. Ventricular dysrhythmias have rarely been reported. Serotonin toxicity (autonomic instability, altered mental status, seizures, muscle rigidity, hyperreflexia, and hyperthermia) may occur; however, most reported cases involve patients using multiple serotonergic agents.

0.2.20)

A) Fluoxetine is classified as FDA pregnancy category C. Fluoxetine/olanzapine combination is classified by the manufacturer as FDA pregnancy category C. There was no significant association between the use of SSRIs in early pregnancy and the risks of birth defects, including congenital heart defects, according to a later population-based case-control study. Neonatal exposure to fluoxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs) has led to complications requiring prolonged hospitalization, respiratory support, and tube feeding, particularly when that exposure occurs in the third trimester. Clinical findings have included cyanosis, apnea, seizures, tremor, and constant crying, and the clinical scenario is reflective of serotonin syndrome in some cases. An increased risk for social-behavioral abnormalities at 2 to 6 years of age was reported in children exposed to SSRIs or SNRIs in utero who developed neonatal abstinence syndrome (NAS) at birth.

0.2.21)

A) At the time of this review, the manufacturer does not report any carcinogenic potential for fluoxetine.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Primarily supportive care; a single dose of activated charcoal may be helpful in patients presenting shortly after ingestion.

B) MANAGEMENT OF SEVERE TOXICITY

1) Consider a single dose of activated charcoal if patients present early after ingestion. In case of significant CNS depression, perform orotracheal intubation for airway protection prior to giving charcoal. Use primarily benzodiazepines for serotonin toxicity. In case of autonomic instability, severe muscle rigidity, and significant hyperthermia consider intubation and muscle paralysis.

C) DECONTAMINATION

1) PREHOSPITAL: GI decontamination is not recommended because of potential for somnolence and seizures.
2) HOSPITAL: Single dose activated charcoal if recent, substantial ingestion, and patient is able to protect airway.

D) AIRWAY MANAGEMENT

1) Early orotracheal intubation in patients with signs of severe intoxication (CNS depression, seizures, severe serotonin toxicity).

E) ANTIDOTE

1) None.

F) SEIZURES

1) Use IV benzodiazepines or barbiturates as needed.

G) SEROTONIN SYNDROME

1) Treat with benzodiazepines. In severe cases cyproheptadine is sometimes used. Cyproheptadine, Adult: 12 mg orally initially followed by 2 mg every 2 hours if symptoms persist, maximum 32 mg/day, maintenance dose 8 mg every 6 hours. Pediatric: 0.25 mg/kg/day divided every 6 hours, maximum 12 mg/day.

H) ENHANCED ELIMINATION

1) There is no role for repeat-dose activated charcoal, hemodialysis or hemoperfusion.

I) PATIENT DISPOSITION

1) HOME CRITERIA: Children and adults with mild symptoms (eg, vomiting, mydriasis, diaphoresis, mild somnolence) with inadvertent ingestions of up to 100 mg fluoxetine can be managed at home. A patient on chronic fluoxetine therapy may be managed at home if there are only mild symptoms, the ingestion is inadvertent and less than 5 times that patient’s single therapeutic dose.
2) OBSERVATION CRITERIA: Any patient who overdoses in suicidal attempt or who develops more than mild symptoms should be sent to a healthcare facility for evaluation and treatment. For fluoxetine naive patients with ingestion more than 100 mg and for patients on chronic fluoxetine therapy with an ingestion of more than five times that patient’s single therapeutic dose, prompt referral to a healthcare facility is necessary for evaluation and treatment. Patients should be observed for 6 hours. With ingestion of extended-release formulations, absorption is delayed by 1 to 2 hours at therapeutic doses and may warrant longer observation times (8 to 12 hours).
3) ADMISSION CRITERIA: Patients with persistent mental status changes, seizures or dysrhythmias should be admitted.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in decision making whether or not admission is advisable, managing patients with severe toxicity (CNS depression, seizures, serotonin toxicity), or in whom the diagnosis is not clear.

J) PHARMACOKINETICS

1) Bioavailability is almost 100%. Maximal plasma levels are reached after 6 to 8 hours, protein binding is 95%, elimination primarily occurs by hepatic metabolism (CYP 2D6, 2C). The elimination half life is 4 to 6 days. Tmax of extended release formulations is delayed by 1 to 2 hours. The elimination half-life of the active metabolite norfluoxetine ranges from 7 to 15 days.

K) DIFFERENTIAL DIAGNOSIS

1) Differential diagnosis is wide given the unspecific symptoms and signs in fluoxetine overdose. Consider poisoning with other CNS depressants, serotonergic agents, and CNS infection.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Heent

3.4.3)

A) BLURRED VISION

1) WITH POISONING/EXPOSURE

a) Blurred vision has been reported after overdose (Technical Information, 1987).
b) CASE REPORT: A 15-year-old adolescent girl developed blurred vision after ingesting 900 mg of fluoxetine (Braitberg & Curry, 1995).

2) WITH THERAPEUTIC USE

a) Blurred vision has been a minor side effect of fluoxetine therapy (Prod Info Prozac(R), fluoxetine, 1999; Technical Information, 1987).

B) NYSTAGMUS

1) WITH POISONING/EXPOSURE

a) Nystagmus was noted in 1 patient who ingested approximately 340 mg of fluoxetine (Technical Information, 1987).

Cardiovascular

3.5.2)

A) CONDUCTION DISORDER OF THE HEART

1) WITH THERAPEUTIC USE

a) CASE SERIES: ECGs of patients taking fluoxetine showed none of the prolongation of PR and QRS intervals seen with the tricyclics. Fluoxetine in therapeutic doses had no significant clinical effect on the ECG. Normal ECG readings were also found in two patients who ingested more than the recommend daily dose of fluoxetine; one patient ingested 1000 mg alone and the other ingested 200 mg with 15 oz of rum (Fisch, 1985).
b) CASE SERIES: It has been reported that 3 elderly female patients, with underlying life-threatening pulmonary and cardiac disorders, died of cardiac dysrhythmias within 10 days of beginning fluoxetine treatment. A clear relationship between the death of these patients and the start of fluoxetine therapy was not established (Spier & Frontera, 1991).
c) CASE REPORT: A 74-year-old woman developed syncope and torsade de pointes requiring cardioversion 3 weeks after being switched from amitriptyline to fluoxetine (Appleby et al, 1995). ECG revealed QTc prolongation. Symptoms stopped when fluoxetine was discontinued, but the ECG was not repeated.

2) WITH POISONING/EXPOSURE

a) Cardiovascular side effects associated with fluoxetine overdose include hypertension, ECG abnormalities, and syncope (Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
b) CASE REPORT: A 33-year-old, healthy man developed a prolonged QRS interval (0.110 seconds) and a QTc interval of 0.458 seconds within 30 minutes following an overdose of 120 fluoxetine 20 mg capsules and 100 acetaminophen 500 mg tablets. The QRS narrowed promptly (0.09 seconds) after an intravenous bolus of 50 mEq sodium bicarbonate (Graudins et al, 1997).
c) CASE REPORT: A patient ingested fluoxetine with indomethacin and developed premature ventricular contractions, bigeminy, and ventricular tachycardia, all responsive to lidocaine (Borys et al, 1990).
d) CASE REPORT: A 22-year-old woman presented to the emergency department with bradycardia (heart rate 59) and QTc prolongation (0.456 seconds) 5 hours after ingesting 1.2 to 1.4 grams of fluoxetine. Bigeminy and further QTc prolongation (0.495 seconds) developed 12 hours after ingestion and deteriorated to ventricular tachycardia responsive to lidocaine and sodium bicarbonate. QTc remained prolonged (0.483 seconds) 4 days after exposure (Hofman & Liu, 1994).
e) CASE REPORT: A 19-year-old man developed two episodes of atrial flutter, each lasting approximately 15 minutes, after ingesting 140 mg of loxapine and 600 mg of fluoxetine (Roberge & Martin, 1994).
f) CASE SERIES: Of 9 patients reported to have ingested fluoxetine alone, 1 patient was reported to have ST-segment depression (Technical Information, 1987). Of another group of 37 patients, 1 had a junctional rhythm, and the rest of the 23 who had ECG studies showed sinus rhythm (Borys et al, 1990).

B) BRADYCARDIA

1) WITH THERAPEUTIC USE

a) A slightly decreased heart rate has been seen in both animal and human studies (Fisch, 1985; Ellison et al, 1990; Borys et al, 1990).
b) A case of bradycardia in an elderly woman treated with fluoxetine 20 mg/day was reported. It has been suggested that these effects are dose-related and therefore dosage should be reduced in the elderly or patients with a history of cardiac problems (Buff et al, 1991; Friedman, 1991).

2) WITH POISONING/EXPOSURE

a) A slightly decreased heart rate has been seen in both animal and human studies (Fisch, 1985; Ellison et al, 1990; Borys et al, 1990).

C) TACHYARRHYTHMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Supraventricular tachycardia and hypotension were associated with maintenance therapy of fluoxetine 20 mg/day in a 54-year-old woman (Gardner et al, 1991). Cardiac symptoms and palpitations have not recurred in 25 months of follow-up. She received verapamil initially, which was discontinued 6 weeks later.

2) WITH POISONING/EXPOSURE

a) Tachycardia is common after overdose (Braitberg & Curry, 1995).
b) CASE SERIES: Tachycardia developed in 15 of 87 patients after overdose with fluoxetine alone (Borys et al, 1992).

D) ELECTROCARDIOGRAM ABNORMAL

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 52-year-old man developed ECG changes of broad based T waves and QTc prolongation (0.56 sec) after beginning fluoxetine 40 mg/day. The QTc returned to normal (0.38 sec) 10 days after fluoxetine was discontinued (Varriale, 2001).

E) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) CASE SERIES: After ingesting 340 to 1500 mg, 3 of 37 patients reported for purely fluoxetine poisoning had diastolic blood pressures greater than 100 mmHg (Borys et al, 1990).

F) VASCULITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: An 83-year-old woman developed pain, swelling, and tenderness of her arms with malaise, lethargy, nausea, and vomiting 3 days after beginning fluoxetine therapy. Muscle biopsy showed acute myositis and extensive muscle infarction. Fluoxetine was discontinued, and the patient died suddenly on the 7th hospital day of a ruptured abdominal aortic aneurysm. Postmortem muscle biopsy showed muscle necrosis and necrotizing vasculitis of the small- and medium-sized arteries (Fisher et al, 1999).

Respiratory

3.6.2)

A) INFLUENZA-LIKE SYMPTOMS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 19-year-old woman developed flu-like symptoms (dyspnea, malaise, myalgia, arthralgia, chill, headache, nasal congestion, cough), along with urticaria, maculopapular rash, and angioedema 2 days following ingestion of 680 mg of fluoxetine.

1) Although this may have represented a hypersensitivity reaction, another possible explanation is a dose-related phenomenon associated with peak metabolite (norfluoxetine) serum concentrations (Kim & Pentel, 1989).

B) DISORDER OF RESPIRATORY SYSTEM

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 62-year-old woman developed cough and dyspnea 4 months after beginning fluoxetine (Gonzalez-Rothi et al, 1995a). Symptoms resolved when fluoxetine was discontinued and recurred within 5 days when it was restarted. She developed interstitial infiltrates and restrictive lung disease; bronchoalveolar lavage was suggestive of hypersensitivity pneumonitis.

C) DISORDER OF RESPIRATORY SYSTEM

1) WITH POISONING/EXPOSURE

a) Pulmonary dysfunction has been reported with fluoxetine overdose (Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH POISONING/EXPOSURE

a) CNS effects associated with fluoxetine overdose include: abnormal gait, confusion, mania, movement disorders, seizures, somnolence, and vertigo (Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).

B) SEIZURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: An 84-year-old woman was reported to have a single, brief, generalized seizure 5 days after initiating therapy with fluoxetine 20 mg/day. The patient had no prior history of seizures but had other concurrent illnesses that may have been contributory (Weber, 1989).
b) CASE REPORTS: Two patients concurrently taking lithium and fluoxetine in therapeutic doses for depression and suicidal ideation experienced seizures following ingestion of LSD (Jackson & Hornfeldt, 1991).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Two generalized seizures of 2- to 3-minute duration were seen 9 hours after ingestion of 3 g of fluoxetine. The patient had a plasma concentration of 2461 nanograms (ng)/mL; aspirin and alcohol were coingestants in this case. The patient also had a prior history of seizures (Wernicke, 1985).
b) CASE REPORT: A single, generalized seizure occurred 3.5 hours after ingestion of 1880 mg by a 12-year-old boy (Riddle et al, 1989).
c) CASE REPORT: A tonic-clonic seizure was observed in a 27-year-old woman following coingestion of fluoxetine 80 mg and phenelzine 150 mg. This was apparently because of an adverse interaction between these drugs (Chiang & Smilkstein, 1989).
d) CASE REPORT: One patient who ingested fluoxetine with 2 g of meprobamate had seizures (Borys et al, 1990).
e) CASE REPORT: Tonic-clonic seizures developed in a 15-year-old adolescent girl 10 hours after ingesting 900 mg of fluoxetine (Braitberg & Curry, 1995).
f) CASE REPORT: A 26-year-old man ingested 1200 mg of fluoxetine and developed generalized tonic-clonic seizures approximately 3 hours postingestion. EEGs performed 1 and 7 days after the event were normal (Gross et al, 1998).
g) CASE REPORT: A 37-year-old woman developed a single, generalized tonic-clonic seizure approximately 3 hours after ingesting 1400 mg of fluoxetine along with alcohol. Fluoxetine and norfluoxetine serum levels were 922 ng/mL and 379 ng/mL, respectively, 6 hours postingestion. The patient was observed overnight with no other seizure activity (Suchard, 2008).

C) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Of 9 patients reported to have ingested fluoxetine alone, 1 patient who ingested 340 mg was comatose; drowsiness was reported in a 19-year-old who ingested 1000 to 1200 mg (Technical Information, 1987). Drowsiness developed in 14 of 87 patients after overdose with fluoxetine alone (Borys et al, 1992).

D) ATAXIA

1) WITH THERAPEUTIC USE

a) Ataxia and tremor were side effects seen with some frequency with fluoxetine therapy (Wernicke, 1985).

2) WITH POISONING/EXPOSURE

a) Ataxia and tremor were seen in overdose (Borys et al, 1992).

1) Tremor was seen in a 26-year-old who ingested 220 mg/day for 9 days (Technical Information, 1987).

E) DIZZINESS

1) WITH THERAPEUTIC USE

a) CASE SERIES: Dizziness and blurred vision were reported in 25% of patients taking therapeutic dosages of fluoxetine (Borys et al, 1990; Gorman et al, 1987).

2) WITH POISONING/EXPOSURE

a) CASE SERIES: Dizziness and blurred vision were reported in 1 of 37 patients after fluoxetine overdose (Borys et al, 1990; Gorman et al, 1987).

F) CENTRAL STIMULANT ADVERSE REACTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 4-year-old girl developed hypervigilance, nervousness, psychomotor agitation, and abnormal jerking movements after ingesting an unknown quantity of fluoxetine (Freierabend, 1995). This was followed by a several-minute period of unresponsiveness.

G) SYNCOPE

1) WITH THERAPEUTIC USE

a) Syncope has been reported at dosages of 20 mg to 80 mg/day (Ellison et al, 1990).

H) SEROTONIN SYNDROME

1) WITH THERAPEUTIC USE

a) Fluoxetine, a potent inhibitor of serotonin uptake, may interact with other pharmaceuticals or circumstances that cause serotonin release. Because of fluoxetine's long half-life, which results in significant plasma levels persisting many weeks after fluoxetine discontinuation, caution must be used with concomitant use of serotonin-increasing medications. A washout period of at least 5 weeks after discontinuing fluoxetine and beginning a drug that may increase serotonin levels is recommended (Lane & Baldwin, 1997).

1) Serotonin syndrome has been described from fluoxetine interactions with irreversible MAOIs, moclobemide, tryptophan, selegiline, nefazodone, tramadol, and lithium (Mitchell, 1997; Smith & Wenegrat, 2000; Kesavan & Sobala, 1999).

b) SIGNS may include hyperreflexia, hyperthermia, restlessness, diaphoresis, unsteady gait, and myoclonic jerking. This is contrasted with the neuroleptic malignant syndrome, which usually includes rigidity and autonomic dysfunction (Perse et al, 1991).
c) CASE REPORT: A 39-year-old woman developed mental status changes, diaphoresis, diarrhea, and slurred speech 1 day after discontinuing fluoxetine and clonazepam and starting on venlafaxine and lorazepam. This is reported as a case of serotonin syndrome with the use of fluoxetine that did not involve the concomitant use of an MAOI (Bhatara et al, 1998).
d) CASE REPORT: A 37-year-old man taking fluoxetine 20 mg/day developed confusion, diaphoresis, incoordination, diarrhea, and myoclonus after buspirone was added to his drug regimen (Manos, 2000).
e) CASE REPORT: A 50-year-old man developed lethargy, disorientation, vomiting, myoclonus, and visual hallucinations after adding nefazodone to fluoxetine therapy. Symptoms completely resolved 3 days after therapy was discontinued (Smith & Wenegrat, 2000).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 40-year-old woman developed CNS depression, tremors, decerebrate posturing, hyperthermia, hypotension, DIC, metabolic acidosis, rhabdomyolysis, and multiple organ failure after overdose of moclobemide, clomipramine and fluoxetine (Power et al, 1995).

I) MULTIPLE SCLEROSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Exacerbation of symptoms of multiple sclerosis (arm numbness and grogginess) developed in a 41-year-old woman 10 hours after beginning fluoxetine and progressed over the next 4 days of therapy (Browning, 1990). Symptoms returned to baseline after discontinuing therapy.

J) DREAM DISORDER

1) WITH THERAPEUTIC USE

a) Vivid nightmares and night terrors have been reported with therapeutic use (Lepkifker et al, 1995).

K) EXTRAPYRAMIDAL DISEASE

1) WITH THERAPEUTIC USE

a) Extrapyramidal symptoms have been reported in patients taking fluoxetine, but they are not common (Arya, 1994).
b) CASE SERIES: In a series of 5555 patients taking fluoxetine therapeutically, 15 developed extrapyramidal effects (Coulter & Pillans, 1995). Eight of these were taking other drugs that may have contributed to these effects.

L) HALLUCINATIONS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 38-year-old man developed a complex visual hallucination, described as a blue-green central disc that nearly filled the visual fields, with a dynamic yellow central portion, peripheral yellow regions, and a red vertical bar in the left visual field of both eyes. The visual pattern was present daily on awakening and would last 30 to 40 seconds. The pattern occurred initially with sertraline therapy and recurred when fluoxetine was substituted. It gradually disappeared when both were discontinued and nefazodone was substituted (Bourgeois et al, 1998).

3.7.3)

A) ANIMAL STUDIES

1) SEIZURES

a) Seizure potential was evaluated in animals during high-dose administration. With doses near 250 mg/kg in one study and 450 mg/kg in another, 50% of the animals had seizures (Wernicke, 1985).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea is a common, mild to moderately severe side effect seen with therapeutic dosing (Wernicke, 1985).

2) WITH POISONING/EXPOSURE

a) Nausea is a common, mild to moderately severe side effect seen with excessive dosing (Borys et al, 1992).
b) CASE REPORTS: Spontaneous emesis developed in 1 patient who ingested 900 mg to 1200 mg with no reported coingestants (Technical Information, 1987), and another who ingested 2000 mg (Moore & Rodrigues, 1990).

B) DIARRHEA

1) WITH THERAPEUTIC USE

a) CASE SERIES: Diarrhea developed in 38 percent of patients receiving therapeutic doses of fluoxetine for panic attacks (Gorman et al, 1987).

2) WITH POISONING/EXPOSURE

a) CASE SERIES: Diarrhea was reported in 2 of 37 patients with fluoxetine overdose (Borys et al, 1990).

C) LOSS OF APPETITE

1) WITH THERAPEUTIC USE

a) Fluoxetine has been shown to cause anorexia with resultant weight loss in overweight, nondepressed individuals at dosages of 20 to 80 mg/day (Ferguson & Feighner, 1987).

D) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE

1) WITH THERAPEUTIC USE

a) CASE REPORTS: Two cases of stomatitis related to fluoxetine intake in the treatment of depression have been reported. A 24-year-old woman had been taking fluoxetine for 6 months and experienced 6 recurrent episodes of stomatitis without complete remission between outbreaks. When fluoxetine was discontinued, the stomatitis resolved completely. A rechallenge with fluoxetine 7 months later caused the stomatitis to recur. A second case was reported in a 41-year-old woman taking fluoxetine and bentazepam. After both drugs were discontinued, the stomatitis resolved in 2 days. She refused rechallenge with fluoxetine (Palop et al, 1997).

Hepatic

3.9.2)

A) TOXIC HEPATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 35-year-old man with histologically severe hepatitis had a positive antibody against hepatitis C, but no hepatitis C viral RNA could be detected by branch-chain DNA or reverse-transcription polymerase chain reaction. He did not respond to prednisone therapy but did respond when his fluoxetine was discontinued. In retrospect, researchers found a strong correlation between elevated ALT and fluoxetine dose during the 10 months prior to presentation. They postulated that his chronic hepatitis was due to fluoxetine therapy (Johnston & Wheeler, 1997).
b) Several other cases of hepatitis associated with therapeutic fluoxetine use have been reported (Cai et al, 1999; Anon, 1996).

Hematologic

3.13.2)

A) PLATELET AGGREGATION

1) WITH THERAPEUTIC USE

a) Fluoxetine blocks 5-HT reuptake in platelets and may lead to platelet dysfunction.
b) CASE REPORT: A patient with a minor history of bleeding disorder (occasional epistaxis and bruising) developed a prolonged bleeding time and petechiae while taking fluoxetine 20 mg every other day for two years.

1) Her platelet count, prothrombin time, and von Willebrand factors were normal, and she was on no other medication.
2) The patient was taken off fluoxetine, and bleeding time returned to normal. After a return to fluoxetine therapy at the same dosage, prolonged bleeding time and petechiae again returned (Humphries et al, 1990).

B) APLASTIC ANEMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 28-year-old man taking fluoxetine 20 mg twice daily for 6 weeks developed aplastic anemia. The bone marrow biopsy showed hypoplasia with severe depression of megakaryocytes and myeloid cells and moderate depression of erythroid cell line. Fluoxetine was discontinued on the 3rd hospital day, and his blood count rose slowly.

1) Twenty-five days after admission, fluoxetine 20 mg once daily was reinstituted, but 5 days later was withdrawn because of a fall in peripheral blood cell counts. His hematological abnormalities returned to normal within 12 days, and pancytopenia had not recurred during 6 months follow-up (Bosch & Vera, 1998).

C) ECCHYMOSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 31-year-old woman developed easy bruising with a normal prothrombin time, partial thromboplastin time, and CBC after beginning fluoxetine. Bleeding time was not assessed. The authors speculated that the bruising was a result of suppression of serotonin-induced platelet aggregation (Pai & Kelly, 1996).

Dermatologic

3.14.2)

A) URTICARIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Urticaria was reported in a 48-year-old man who ingested 280 mg over 2 days (Technical Information, 1987).

B) ERUPTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: Bullous pemphigoid was associated with fluoxetine therapy in a 75-year-old woman; it resolved with discontinuation of fluoxetine (Rault et al, 1999).

Immunologic

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH POISONING/EXPOSURE

B) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) Urticaria, angioedema, bronchospasm, and other anaphylactoid events have been reported (Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).

C) SERUM SICKNESS DUE TO DRUG

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 16-year-old adolescent girl with depression developed generalized urticarial eruption, difficulty swallowing, arthralgia, and fever (39 degrees Celsius) 48 hours after discontinuing fluoxetine (20 mg/day taken for 4 weeks). Laboratory results showed leukocytosis of 17.5 times 10(3)/mm(3) with neutrophilia. Sinus x-rays showed slight mucosal thickening of the maxillary antra bilaterally. Following supportive treatment, her symptoms improved 72 hours after admission. No subsequent rechallenge with fluoxetine was completed (Shapiro et al, 1997).

Reproductive

3.20.1)

3.20.2)

A) CONGENITAL MALFORMATIONS

1) Data from the case-controlled National Birth Defects Prevention Study (NBDPS) indicated that early maternal exposure (defined as treatment with any SSRI from 1 month before to 3 months after conception) to SSRIs was associated with a significant 2.4 times increased risk of anencephaly, which occurred in 9 exposed infants out of 214, a significant 2.5 times increased risk of craniosynostosis, which occurred in 24 exposed infants out of 432, and a significant 2.8 times increased risk of omphalocele, which occurred in 11 exposed infants out of 181. However, early exposure did not significantly increase the risks of congenital heart defects or most other birth defects. The most commonly used SSRIs reported by control mothers were sertraline, fluoxetine, paroxetine, and citalopram (Alwan et al, 2007). Using an expanded data-set from this study, a follow-up analysis confirmed an association between early maternal exposure to fluoxetine and craniosynostosis, with a significant 1.9 times increased risk. For fluoxetine treatment, significant associations were also seen for ventricular septal defects (1.4 times increased risk) and right ventricular outflow tract obstruction defects (2 times increased risk) in this analysis (Reefhuis et al, 2015).
2) SSRI administration lasting more than 30 days during the second or third lunar month of pregnancy was associated with a significant 80% increased risk of clubfoot occurrence in infants. Escitalopram administration had a significant 190% increased risk, paroxetine administration had a non-significant 820% increased risk, sertraline administration had a non-significant 60% increased risk, fluoxetine administration had a non-significant 30% increased risk, and citalopram administration had a non-significant 10% decreased risk. Because of small numbers of subjects exposed to these SSRIs, the estimated odds ratios were unstable for these agents, especially for paroxetine (Yazdy et al, 2014).

B) LACK OF EFFECT

1) A study of 128 women exposed to fluoxetine during the first trimester showed no increase in major fetal malformations. There was a tendency for women exposed to fluoxetine or tricyclic antidepressants to report more spontaneous abortions than women exposed to no teratogens (Pastuszak et al, 1993).
2) In a study of 796 pregnancies with known fluoxetine exposure during the first trimester, there was no increased risk of major fetal malformations. There was also no increase in the number of spontaneous abortions in fluoxetine-exposed pregnancies (Goldstein DA, 1997).
3) In a study of 267 women exposed to SSRIs, there was no increase in the risk of major malformations or higher rates of miscarriage, stillbirth, or prematurity compared with controls (Kulin et al, 1998).
4) In a study of 64 mother-infant pairs, where there was documented use of fluoxetine some time during the pregnancy, there was no difference found in birth weight and acute neonatal outcome between early trimester exposure vs late trimester exposure. There was a higher frequency of special care nursery admission for infants exposed in late trimester (Cohen et al, 2000).
5) The frequency of congenital anomalies was 3.4% in 544 pregnancies in women voluntarily reporting to the manufacturer, and there was no obvious pattern or clustering of abnormalities in the 28 affected children (Goldstein & Marvel, 1993); the frequency of congenital abnormalities would be considered in the normal range. No consistent pattern of postnatal complications were seen in children whose mothers received fluoxetine during the last trimester of pregnancy (Goldstein, 1995).

C) ANIMAL STUDIES

1) LACK OF EFFECT

a) RATS, RABBITS: Fluoxetine was not teratogenic in rats and rabbits at doses equivalent to 9 and 11 times, respectively, the maximum daily human therapeutic dose (Pohland et al, 1989; Goldstein, 1990).
b) RATS, RABBITS: Fetal viability, weight, and morphology were not affected in rat and rabbit pups born to dams exposed to fluoxetine during gestation (Byrd & Markham, 1994).
c) RATS, RABBITS: No increased malformations occurred in rats or rabbits exposed to 8 or 9 times the usual human therapeutic dose (Byrd et al, 1989; Hoyt et al, 1989).

2) SKIN HEMATOMAS

a) RATS: Rat pups born to dams exposed to fluoxetine during pregnancy had an increased incidence of skin hematomas (Stanford & Patton, 1993).

3.20.3)

A) PREGNANCY CATEGORY

1) Fluoxetine is classified by the manufacturer as FDA pregnancy category C (Prod Info SARAFEM(R) oral tablets, 2009; Prod Info PROZAC(R) oral pulvules, solution, delayed-release capsules, 2009).
2) Fluoxetine/olanzapine combination is classified by the manufacturer as FDA pregnancy category C (Prod Info SYMBYAX oral capsules, 2011).

B) CARDIOVASCULAR ANOMALIES

1) Risk assessment studies of fluoxetine exposure during the first trimester have yielded inconsistent results. There was no evidence of an increased risk for congenital anomalies in more than 10 cohort and case-control studies. In a prospective, cohort study conducted by the European Network of Teratology Information Service, however, there was an increased risk of cardiovascular anomalies in infants following maternal first trimester fluoxetine exposure (n=253) compared with infants of mothers who had no fluoxetine exposure (n=1359). The cardiovascular malformations followed no specific pattern and causality to fluoxetine could not be established (Prod Info SYMBYAX oral capsules, 2011).

C) NEONATAL COMPLICATIONS

1) Infants exposed to fluoxetine and other SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs) late in the third trimester developed neonatal complications. Epidemiological studies showed an increased risk of persistent pulmonary hypertension of the newborn (PPHN) with prenatal exposure to fluoxetine and other SSRIs during pregnancy, a condition associated with considerable neonatal morbidity and mortality. Prenatal exposure late in the third trimester has been linked to complications that required intensive care (eg, prolonged hospitalization, tube feeding, respiratory support), sometimes immediately after delivery. Symptoms have been consistent with either a direct toxic effect of the agent or a possible drug discontinuation syndrome (eg, constant crying; irritability; jitteriness or tremor; hyperreflexia; hypertonia or hypotonia; hypoglycemia; vomiting; feeding difficulties; temperature instability; seizures; or respiratory distress, cyanosis, or apnea). In some cases, clinical findings were consistent with serotonin syndrome (Prod Info PROZAC(R) oral pulvules, oral delayed-release capsules, 2013a).
2) An increased risk for CNS serotonergic symptoms was observed during the first 4 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 were compared to 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 as compared with the control group (8.8 vs 9.4). The only significant difference observed in the vital signs of the newborns was a higher heart rate in the SSRI group at 2 weeks as compared with the controls (mean, 153 vs 141 beats per minute). 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). 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 as compared with the control group (mean, 63 vs 77 mmol/L). 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. 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).

D) 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).

E) HYPOGLYCEMIA

1) A child at 38 weeks of gestation was born to a mother who had been taking fluoxetine during most of her pregnancy. The infant was initially hypoglycemic (33 mg/dL). Four hours after birth, he developed acrocyanosis, tachypnea, and jitteriness. Over the next 7 hours, he developed temperature instability, increasing jitteriness, poor suck, opisthotonic posturing, and lateral roving eye movements. His symptoms peaked at 36 hours of age and resolved by 96 hours. Cord blood fluoxetine level was 26 nanograms (ng)/mL (therapeutic: 40 to 250 ng/mL), and norfluoxetine level was 54 ng/mL (therapeutic: 30 to 325 ng/mL) (Spencer, 1993).

F) 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) and developmental scores (98.9 +/- 11.4 versus 95.7 +/- 9.9, respectively). 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 a significant 3-fold increased risk of social-behavior abnormalities based on the Denver Developmental Screening Test II (DDST-II) (Klinger et al, 2011).

G) NEONATAL INTENSIVE CARE

1) Infants exposed to fluoxetine and other SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs) late in the third trimester developed neonatal complications. Epidemiological studies showed an increased risk of persistent pulmonary hypertension of the newborn (PPHN) with prenatal exposure to fluoxetine and other SSRIs during pregnancy, a condition associated with considerable neonatal morbidity and mortality. Prenatal exposure late in the third trimester has been linked to complications that required intensive care (eg, prolonged hospitalization, tube feeding, respiratory support), sometimes immediately after delivery. Symptoms have been consistent with either a direct toxic effect of the agent or a possible drug discontinuation syndrome (eg, constant crying; irritability; jitteriness or tremor; hyperreflexia; hypertonia or hypotonia; hypoglycemia; vomiting; feeding difficulties; temperature instability; seizures; or respiratory distress, cyanosis, or apnea). In some cases, clinical findings were consistent with serotonin syndrome (Prod Info PROZAC(R) oral pulvules, oral delayed-release capsules, 2013a).
2) 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 to 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's supply) of an SSRI during the period of 1 month before pregnancy to the day pregnancy ended were compared to 1782 controls with no reimbursed drug purchases during the same peripartum period. The mean age of both cohorts was 30 (+/- 7) years. There were more than twice as many smokers and 6 times as many pregnancies induced by artificial reproductive techniques in the SSRI group compared to controls , and mean length of gestation and birth weight were lower in the SSRI group. Malformations, however, were not more common in the SSRI group. Purchases of SSRIs (citalopram, fluoxetine, paroxetine, sertraline, and fluvoxamine) were more common in the first trimester than later in pregnancy, with 525 women purchasing fluoxetine during the first trimester, 232 during the second trimester, 239 during the third, and 65 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). Even after adjusting for confounding variables, the group exposed during the third trimester had a significant 60% increased risk compared with the first-trimester exposed group (Malm et al, 2005).

H) PULMONARY HYPERTENSION

I) QT PROLONGATION

1) A study of prospectively collected data suggests antenatal use of SSRI antidepressants is associated with QTc-interval prolongation in exposed neonates. Between January 2000 and December 2005, researchers compared 52 neonates exposed to SSRIs (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 msec (the widely used upper limit cited by authorities in both pediatric cardiology and neonatology). A pediatric cardiologist blinded to drug exposure interpreted all ECGs using standard statistical analyses. ECG recordings revealed markedly prolonged mean QTc intervals in exposed neonates compared with unexposed neonates (mean, 409 +/- 42 msec vs 392 +/- 29 msec). The mean uncorrected QT interval was 7.5% longer among exposed neonates (mean, 280 +/- 31 msec vs 261 +/- 25 msec). Ten percent (n=5) of exposed neonates had a notable increase in QTc-interval prolongation (greater than 460 msec) compared with none of the unexposed neonates. The longest QTc interval observed was 543 msec (Dubnov-Raz et al, 2008).

J) SKIN DISORDER

1) A preterm infant born to a mother taking fluoxetine during pregnancy showed marked motor automatism and skin manifestations. The serum level in the infant was 92 nanograms/mL. Symptoms resolved in 7 days, and follow-up at 4 months showed normal neurodevelopmental examination (Mohan & Moore, 2000).

K) SPONTANEOUS ABORTION

1) A nested case-controlled study showed that fluoxetine, sertraline, citalopram, fluvoxamine, 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 a significant 68% increased risk of spontaneous abortion 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 alone was associated with a significant 75% 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).
2) In a prospective study of 128 pregnant women taking fluoxetine for depression, rate of miscarriage was nearly 2-fold higher in the treated group. There were no differences in rates of serious birth defects, vaginal vs cesarean deliveries, birth weight, gestational age at delivery, or use of forceps at delivery. Postnatal complications were higher in the treated group, but ongoing follow-up of these children has not revealed any significant neurodevelopmental deficits (Pastuszak et al, 1993) Goren, 1996).

L) OTHER STUDIES

1) In a prospective clinical trial designed to evaluate the pharmacokinetics of fluoxetine and norfluoxetine during pregnancy, delivery, and lactation, pregnancy outcomes were found to be similar in both the control and treated groups. The study compared results from 11 women taking fluoxetine 20 mg to 50 mg/day during pregnancy and lactation with 10 women in the control group who were not exposed to psychotropic medications. Because of increased hepatic blood flow, increased volume of distribution, and decreased binding to plasma proteins, trough plasma concentrations of fluoxetine and norfluoxetine were low. At delivery, umbilical vein concentrations were 65% and 72% of the maternal concentrations. During the early postnatal period, plasma concentrations of fluoxetine and norfluoxetine were still elevated, likely because of the slow development of infant glucuronidation capacity and CYP2D6 enzyme activity. There were no fetal malformations or differences in birth weights between the 2 groups. However, Apgar scores at 15 minutes were lower in the fluoxetine group (Heikkinen et al, 2003).
2) In a prospective study of 228 pregnant women taking fluoxetine, no significant differences in rates of miscarriage or major birth defects were seen, compared with 254 untreated controls. Children exposed during the last trimester had a higher rate of perinatal complications, however (Chambers et al, 1996).

M) ANIMAL STUDIES

1) PLACENTAL BARRIER

a) RATS: Fluoxetine and its major metabolite, norfluoxetine, cross the placenta in rats and are at highest levels in the fetal brain and thymus (Pohland et al, 1989).
b) RATS: In rats, both fluoxetine and norfluoxetine cross the placenta and distribute within the fetus during the periods of organogenesis and post-organogenesis (Pohland et al, 1989).

2) NEONATAL MORTALITY

a) RATS: A slight decrease in neonatal survival was seen in rats exposed to 5 to 9 times the maximum human therapeutic dose; this may have been because of maternal toxicity (HSDB , 1996).
b) RATS: Fluoxetine did not produce significant neurodevelopmental effects in the offspring of Sprague Dawley rats given oral doses up to 12 mg/kg on days 7 through 20 of gestation. The highest dose resulted in reduced litter size and increased neonatal mortality but was also toxic to the dam, as evidenced by maternal weight loss during gestation (Vorhees et al, 1994).

3.20.4)

A) BREAST MILK

1) Fluoxetine and its metabolite, norfluoxetine, are excreted in human breast milk. In 1 case, a maternal fluoxetine plus norfluoxetine plasma concentration of 295 nanograms (ng)/mL resulted in a concentration of 70.4 ng/mL in the breastfeeding infant, with no adverse effects reported. In another case, the infant of a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools 2 days after starting breastfeeding. The infant's fluoxetine and norfluoxetine plasma concentrations were 340 and 208 ng/mL, respectively (Prod Info SARAFEM(R) oral tablets, 2009; Prod Info PROZAC(R) oral pulvules, solution, delayed-release capsules, 2009).
2) No clinically significant changes in platelet 5-hydroxytryptamine (5-HT) transport were reported in 11 infants (mean age, at start the of study, 16.8 weeks) exposed to fluoxetine through maternal breast milk. Determinations of whole-blood 5-HT, fluoxetine, and norfluoxetine levels were made in both infants and mothers prior to initiating fluoxetine doses of 20 mg to 40 mg per day. Postexposure levels were measured at 4 to 12 weeks later. Mean maternal plasma concentrations of fluoxetine were 125 nanograms (ng)/mL, and norfluoxetine was 142 ng/mL. All but 1 infant had plasma fluoxetine levels below 1 ng/mL, and the mean infant plasma concentration of norfluoxetine was 3.2 ng/mL. Mean maternal pre- and post-fluoxetine 5-HT levels were 157 ng/mL and 23 ng/mL. The mean infant pre- and postexposure 5-HT concentrations were 217 ng/mL and 230 ng/mL. Bayley Scale scores were determined for 7 of the infants (age range, 24 to 56 weeks), revealing that 6 infants were within 1 standard deviation of the mean on mental and motor developmental indexes. The investigators concluded that most exclusively breastfed infants will not likely experience changes in platelet 5-HT levels upon maternal fluoxetine use (Epperson et al, 2003).
3) Irritability was noted in a 3-month-old boy within 2 weeks after the mother began fluoxetine 20 mg/day. Untimed plasma/breast milk levels of fluoxetine were 100.5 nanogram (ng)/mL and 28.8 ng/mL, with norfluoxetine levels of 194.5 ng/mL and 41.6 ng/mL (Isenberg, 1990).
4) Breastfeeding while taking fluoxetine is associated with reduced growth that may be of clinical importance in situations in which infant weight gain is already of concern (Chambers et al, 1999).
5) Fluoxetine is present to a small degree in mother's milk. The average infant dose of fluoxetine and its major metabolite, norfluoxetine, from nursing is 6.7% +/- 1.4% of the mother's dose in mg/kg. In a small study on 11 infants, no acute adverse effects were seen in nursing infants whose mothers were receiving fluoxetine (Taddio et al, 1994).
6) In another study of 10 nursing women receiving an average dose of 0.39 mg/kg/day, approximately one-tenth of the adult therapeutic dose was excreted in the breast milk. The average infant dose with a total intake of 1000 mL of milk per day was estimated to be 0.077 mg fluoxetine and 0.084 mg of norfluoxetine, the active metabolite of fluoxetine. Short-term adverse events in the infants were not reported in this study(Taddio et al, 1996).
7) In one study, serum levels were not detected in breastfed infants (6 sertraline and 6 paroxetine) of sertraline- or paroxetine-treated mothers. However, a positive serum level was detected in a breastfed infant of a fluoxetine-treated mother, amounting to a mean of 6.4% of the maternal drug level (Berle et al, 2004).

3.20.5)

A) ANIMAL STUDIES

1) RATS: No adverse effects on fertility were reported in studies of adult rats administered fluoxetine doses up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the maximum recommended human dose on a mg/m(2) basis) (Prod Info SARAFEM(R) oral tablets, 2009). However, adverse effects on fertility were reported in juvenile rats administered fluoxetine (Prod Info PROZAC(R) oral pulvules, solution, delayed-release capsules, 2009).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS54910-89-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) At the time of this review, the manufacturer does not report any carcinogenic potential for fluoxetine.

3.21.4)

A) LACK OF EFFECT

1) There was no evidence of carcinogenicity when rats and mice were given fluoxetine in the diet for 2 years at doses up to 10 and 12 mg/kg/day (approximately 1.2 and 0.7 times, respectively, the maximum recommended human daily dose of 80 mg on a mg/m(2) basis) (Prod Info SYMBYAX(R) oral capsule, 2009; Prod Info SARAFEM(R) oral tablets, 2009; Prod Info PROZAC(R) oral pulvules, solution, delayed-release capsules, 2009). However, analysis of the data is subject to debate (Hoffman & Long, 1996; Brandes & Cheang, 1996; Brandes & Cheang, 1995).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (CNS depression, seizures, serotonin toxicity).
C) Monitor serum electrolytes and creatinine phosphokinase concentrations in patients with seizures or prolonged CNS depression.
D) Fluoxetine plasma levels are not clinically useful or widely available. No specific lab work is needed in most patients.

Methods

1) Plasma levels of fluoxetine and norfluoxetine may be obtained by gas chromatography with electron-capture detection (Nash et al, 1982; Wong et al, 1990).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with persistent mental status changes, seizures or dysrhythmias should be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) Children and adults with mild symptoms (eg, vomiting, mydriasis, diaphoresis, mild somnolence) with inadvertent ingestions of up to 100 mg fluoxetine can be managed at home. A patient on chronic fluoxetine therapy may be managed at home if there are only mild symptoms, the ingestion is inadvertent, and the ingestion was less than 5 times that patient’s single therapeutic dose. Follow-up for the first 8 hours after ingestion by the poison center is also recommended, and patient's may need to be admitted to a medical care facility if observation cannot be completed (Nelson et al, 2007).
B) In a retrospective study with telephone follow-up of 126 children younger than 6 years of age with acute ingestion of at least 20 mg of fluoxetine only, 116 patients did not develop any signs or symptoms of toxicity. Seven patients who had received ipecac vomited, 3 patients vomited without receiving ipecac, and 1 patient developed sedation. The dose ingested ranged from 20 mg to 400 mg, with 90% of children ingesting 20 to 60 mg. Children who ingest up to 60 milligrams of fluoxetine (or 5 mg/kg) do not require gastric decontamination or medical treatment. These children could be monitored at home for rare adverse effects (Baker & Morgan, 2004).

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Any patient who overdoses in suicidal attempt or who develops more than mild symptoms should be sent to a healthcare facility for evaluation and treatment. For fluoxetine naive patients with ingestion more than 100 mg and for patients on chronic fluoxetine therapy with an ingestion of more than five times that patient’s single therapeutic dose, prompt referral to a healthcare facility is necessary for evaluation and treatment. Patients should be observed for 6 hours (Nelson et al, 2007). With ingestion of extended-release formulations, absorption is delayed by 1 to 2 hours and may warrant longer observation times (8 to 12 hours) (Prod Info PROZAC(R) oral pulvules, oral delayed-release capsules, 2013).

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: GI decontamination is not recommended because of potential for somnolence and seizures.

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

B) GASTRIC LAVAGE

1) Ingestions are rarely life-threatening; gastric lavage is generally NOT warranted.

6.5.3)

A) 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).

B) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (CNS depression, seizures, serotonin toxicity).
3) Monitor serum electrolytes and creatinine phosphokinase concentrations in patients with seizures or prolonged CNS depression.
4) Fluoxetine plasma levels are not clinically useful or widely available. No specific lab work is needed in most patients.

C) WIDE QRS COMPLEX

1) Sodium bicarbonate IV reversed QRS widening that was associated with fluoxetine overdose in 1 case report (Graudins et al, 1997).
2) A reasonable starting dose is 1 to 2 mEq/kg repeated as needed to maintain serum pH 7.45 to 7.55. Monitor ECG, serum electrolytes, and ABGs carefully.

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, 1991a). 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

1) Hemodialysis did not significantly change the plasma concentration of either fluoxetine or norfluoxetine and would not be expected to have a beneficial effect during overdose (Aronoff et al, 1984).

Abstracts

Case Reports

1) Overdose of fluoxetine alone (up to 1200 mg) has produced ST-segment depression and spontaneous emesis but uneventful recovery. Other reports of ingestion of lower doses with or without other drugs (including alcohol) have not produced serious symptoms.

a) Ingestion of 3 g in combination with aspirin resulted in tachycardia, dizziness, blurred vision, unsustained clonus, ECG changes, and generalized seizure activity (9 hours postingestion). The patient recovered following gastric lavage. One report of fatality from a suicide attempt occurred following an unknown amount of fluoxetine ingestion in combination with other drugs (clobazam, amitriptyline, and pentazocine) (Wernicke, 1985).

2) A 19-year-old woman developed flu-like symptoms (dyspnea, malaise, myalgia, arthralgia, chill, headache, nasal congestion, cough), along with urticaria, maculopapular rash, and angioedema 2 days following ingestion of 680 mg of fluoxetine. She had previously been treated with therapeutic doses for 1 month prior to the overdose. No cardiovascular effects were observed. Serial serum fluoxetine levels were not obtained; the fluoxetine level was 456 ng/mL (therapeutic 80 ng/mL) 48 hours postingestion. The corresponding norfluoxetine level was 349 ng/mL (therapeutic 150 ng/mL). Although this may have represented a hypersensitivity reaction, another possible explanation is a dose-related phenomenon associated with peak metabolite (norfluoxetine) serum concentrations (Kim & Pentel, 1989).

1) A 12-year-old boy ingested approximately 1880 mg (26 mg/kg) of fluoxetine was given syrup of ipecac 45 to 75 minutes postingestion and had a generalized seizure 3.5 hours postingestion. Following the seizure, he was sleepy and complained of nausea and abdominal pain. The ECG showed depressed ST segments with no other abnormality. The following morning he had blurred vision, headache, and dizziness. Plasma levels obtained at 90 minutes, 15 hours, and 66 hours postingestion were 427.8 ng/mL, 1142 ng/mL, and 449.5 ng/mL (Riddle et al, 1989).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) FLUOXETINE

1) The recommended dosage range is 10 mg to 80 mg once daily or in divided doses. Recommended dosage varies by indication (Prod Info PROZAC(R) oral capsules, oral delayed release capsules, 2014; Prod Info SARAFEM(R) oral tablets, 2014; Prod Info fluoxetine HCl oral solution, 2012). The weekly capsule dose is 90 mg once a week, starting 7 days after the last daily dose of 20 mg (Prod Info PROZAC(R) oral capsules, oral delayed release capsules, 2014).

B) FLUOXETINE WITH OLANZAPINE

1) DEPRESSIVE EPISODES ASSOCIATED WITH BIPOLAR I DISORDER

a) The initial recommended dose is olanzapine 6 mg plus fluoxetine 25 mg orally once daily each evening. The usual range is olanzapine 6 to 12 mg/fluoxetine 25 to 50 mg orally once daily each evening. MAX DOSE: Olanzapine 18 mg plus fluoxetine 75 mg (Prod Info SYMBYAX(R) oral capsules, 2015).

2) TREATMENT RESISTANT DEPRESSION

a) The initial recommended dose is olanzapine 6 mg plus fluoxetine 25 mg orally once daily each evening. The usual range is olanzapine 6 to 18 mg/fluoxetine 25 to 50 mg orally once daily each evening. MAX DOSE: Olanzapine 18 mg/fluoxetine 75 mg (Prod Info SYMBYAX(R) oral capsules, 2015).

7.2.2)

A) FLUOXETINE

1) MAJOR DEPRESSIVE DISORDER

a) 8 TO 18 YEARS OF AGE: The recommended dosage for fluoxetine monotherapy is 10 to 20 mg once daily (Prod Info PROZAC(R) oral capsules, oral delayed release capsules, 2014; Prod Info fluoxetine HCl oral solution, 2012).
b) LESS THAN 8 YEARS OF AGE: Safety and efficacy of fluoxetine have not been established (Prod Info PROZAC(R) oral capsules, oral delayed release capsules, 2014; Prod Info fluoxetine HCl oral solution, 2012).

2) OBSESSIVE COMPULSIVE DISORDER

a) ADOLESCENTS AND HIGHER-WEIGHT CHILDREN 7 YEARS AND OLDER: The recommended dosage range is 10 to 60 mg daily (Prod Info PROZAC(R) oral capsules, oral delayed release capsules, 2014; Prod Info fluoxetine HCl oral solution, 2012).
b) LOWER-WEIGHT CHILDREN 7 YEARS AND OLDER: The recommended dosage range is 10 to 30 mg daily (Prod Info PROZAC(R) oral capsules, oral delayed release capsules, 2014; Prod Info fluoxetine HCl oral solution, 2012).
c) LESS THAN 7 YEARS OF AGE: Safety and efficacy have not been established (Prod Info PROZAC(R) oral capsules, oral delayed release capsules, 2014; Prod Info fluoxetine HCl oral solution, 2012).

3) PREMENSTRUAL DYSPHORIC DISORDER

a) Safety and efficacy have not been established in pediatric patients (Prod Info PROZAC(R) oral capsules, oral delayed release capsules, 2014; Prod Info SARAFEM(R) oral tablets, 2014; Prod Info fluoxetine HCl oral solution, 2012).

B) FLUOXETINE WITH OLANZAPINE

1) DEPRESSIVE EPISODES ASSOCIATED WITH BIPOLAR I DISORDER

a) 10 TO 17 YEARS OF AGE: The initial recommended dose is olanzapine 3 mg plus fluoxetine 25 mg orally once daily each evening. The usual range is olanzapine 3 to 12 mg/fluoxetine 25 to 50 mg orally once daily each evening (Prod Info SYMBYAX(R) oral capsules, 2015).
b) LESS THAN 10 YEARS OF AGE: Safety and efficacy of olanzapine and fluoxetine combination have not been established (Prod Info SYMBYAX(R) oral capsules, 2015).

2) TREATMENT RESISTANT DEPRESSION

a) Safety and efficacy of olanzapine and fluoxetine combination have not been established in children younger than 18 years (Prod Info SYMBYAX(R) oral capsules, 2015).

Minimum Lethal Exposure

1) An adult died after an ingestion of 520 mg of fluoxetine alone; causality could not be established (Prod Info PROZAC(R) oral pulvules, delayed-release capsules, 2011).

a) In a retrospective review of data reported to the FDA and Toxic Exposure Surveillance System (TESS) of the American Association of Poison Control Centers, ingestions of 260 mg of fluoxetine alone were reported to be associated with deaths; direct causality could not be determined (Nelson et al, 2007).

2) The estimated human lethal dose of fluoxetine is 1200 to 2000 mg (60 to 100 capsules of 20 mg) (Kincaid et al, 1990).
3) Two deaths have been reported following fluoxetine overdose; however, both patients had other contributory causes (Technical Information, 1987).

a) A 42-year-old woman reported to ingest 1600 mg of fluoxetine along with maprotiline was found dead; postmortem concentrations were fluoxetine 4570 nanograms(ng)/mL and maprotiline 4180 ng/mL (Technical Information, 1987).
b) In the second case, a 24-year-old woman was found dead with a piece of plastic wrap on her face and a partially empty bottle of fluoxetine. The estimated amount ingested was 1580 mg. A preliminary autopsy report showed some signs of asphyxia and a fluoxetine level of 1934 ng/mL (Technical Information, 1987).

1) Lethal seizures were seen in 50% of various animals given 200 to 700 mg/kg. The exact dose needed is species-dependent (Wernicke, 1985).

Maximum Tolerated Exposure

1) Based on manufacturer data, an adult survived an ingestion of 8 g of fluoxetine and recovered (Prod Info PROZAC(R) oral pulvules, delayed-release capsules, 2011).

1) Acute ingestions in adults of 300 to 440 mg, with no coingestants, resulted in no reported signs or symptoms in 2 patients. Coma was reported in 1 patient with a questionable history of ingestion of 340 mg. Ingestion of 900 to 1200 mg resulted in minor ECG changes (Technical Information, 1987).
2) CASE REPORT: A woman with a history of epilepsy experienced generalized seizures, ECG changes and tachycardia, dizziness, and blurred vision after ingesting approximately 3 grams of fluoxetine (Perse et al, 1991).
3) CASE REPORT: A 33-year-old man coingested 120 fluoxetine 20 mg capsules (2400 mg total) and 100 acetaminophen 500 mg tablets and developed QRS prolongation that was responsive to sodium bicarbonate IV(Graudins et al, 1997).
4) CASE REPORT: A 37-year-old woman developed a single, generalized tonic-clonic seizure approximately 3 hours after ingesting 1400 mg fluoxetine along with alcohol. Fluoxetine and norfluoxetine serum levels were 922 ng/mL and 379 ng/mL, respectively, 6 hours postingestion (Suchard, 2008).

1) In a retrospective study with telephone follow-up of 126 children younger than 6 years of age with acute ingestion of at least 20 mg of fluoxetine only, 116 patients did not develop any signs or symptoms of toxicity. Of these, 7 patients who had received ipecac vomited, 3 patients vomited without receiving ipecac, and 1 patient developed sedation. The dose ingested ranged from 20 mg to 400 mg, with 90% of children ingesting 20 to 60 mg. Children who ingest up to 60 mg of fluoxetine (or 5 mg/kg) do not require gastric decontamination or medical treatment. These children can be monitored at home for rare adverse effects (Baker & Morgan, 2004).
2) CASE REPORT: A 12-year-old boy who ingested 1880 mg of fluoxetine (26 mg/kg) had a single seizure, depressed sinus tachycardia segments on ECG, nausea, dizziness, blurred vision, and headache (Riddle et al, 1989).
3) Acute ingestion of up to 100 mg is not expected to cause toxicity (Nelson et al, 2007).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) HUMAN: Normal therapeutic values are approximately 400 nanograms (ng)/mL (Wernicke, 1985). A daily dosing of 60 mg would be expected to result in a steady-state plasma range of 103 to 282 mcg/L of fluoxetine and 47 to 181 mcg/L of norfluoxetine.
b) ADULT: A fluoxetine and norfluoxetine serum level of 922 ng/mL and 379 ng/mL, respectively, were reported in a 37-year-old woman 6 hours after ingesting fluoxetine 1400 mg along with alcohol in a suicide attempt. She experienced a single, generalized tonic-clonic seizure approximately 3 hours postingestion (Suchard, 2008).
c) PEDIATRIC: A serum fluoxetine level of 126 ng/mL and a serum norfluoxetine level, a metabolite, of 126 ng/mL were reported in a newborn exposed to fluoxetine in utero (mother took fluoxetine 40 mg daily throughout pregnancy). The newborn was displaying withdrawal symptoms approximately 12 hours after birth (Kwon & Lefkowitz, 2008).
d) FATALITIES

1) Plasma concentrations in 2 fatal cases were 1.93 mg/L and 4.57 mg/L (Rohrig & Prouty, 1989). The heart blood concentration in a case of fatal combined ethanol/fluoxetine toxicity was 0.8 mg/L (Rohrig & Prouty, 1989).
2) Fluoxetine and norfluoxetine concentrations found in blood were 6000 and 5000 ng/mL, respectively, in a 58-year-old found dead of a suspected fluoxetine overdose (Kincaid et al, 1990).
3) Serum fluoxetine and norfluoxetine levels were 1956 mcg/L and 416 mcg/L, respectively, 11 hours after ingestion in a 15-year-old adolescent who developed seizures after fluoxetine overdose (Braitberg & Curry, 1995).
4) In a series of 168 coroners' cases in whom SSRIs were detected, fluoxetine was considered a primary contributing factor in 4 deaths, with blood levels typically greater than 1 mg/L. Fluoxetine and norfluoxetine levels were 3.67 mg/L and 0.38 mg/L, respectively, in the 1 case certified as a fluoxetine overdose (Goeringer et al, 2000).

e) FORENSIC

1) Roettger (1990) recommends that femoral blood and liver should be analyzed for fluoxetine levels in the postmortem analysis (Roettger, 1990).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) References: Stark et al, 1985

1) LD50- (ORAL)MOUSE:

a) 248 mg/kg

2) LD50- (ORAL)RAT:

a) 452 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.3)

A) Five of six dogs purposely overdosed with oral fluoxetine experienced grand mal seizures, which were alleviated by administration of diazepam IV (Prod Info PROZAC(R) oral pulvules, solution, delayed-release capsules, 2009).

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm, and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) Remove the patient and other animals from the source of contamination.
5) Treatment should always be done on the advice and with the consultation of a veterinarian. Additional information regarding treatment of poisoned animals can be obtained from an American Board of Veterinary Toxicology-certified veterinary toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or from the National Animal Poison Control Center.
6) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

a) EMESIS AND LAVAGE: If within 2 hours of exposure, induce emesis with 1 to 2 mL/kg syrup of ipecac orally. Dogs may vomit more readily with 1 tablet (6 mg) apomorphine diluted in 3 to 5 mL water and instilled into the conjunctival sac or given orally.

1) Dogs also may be given apomorphine IV at 40 mcg/kg, although this route may not be as effective. Do not use an emetic if the animal is hypoxic.
2) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large-bore stomach tube and instill 5 to 10 mL/kg water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ACTIVATED CHARCOAL: Administer activated charcoal, 2 g/kg orally or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary, tracheal intubation.
c) CATHARTIC: Administer a dose of a saline cathartic, such as magnesium or sodium sulfate (sodium sulfate dose is 1 g/kg). If access to these agents is limited, give 5 to 15 mL magnesium oxide (milk of magnesia) orally for dilution.

11.2.5)

A) GENERAL TREATMENT

1) MAINTAIN VITAL FUNCTIONS as necessary.
2) SEIZURES

a) DIAZEPAM: Dosage of diazepam for DOGS & CATS is 0.5 mg/kg IV or bolus; may repeat every 10 minutes for 4 total doses. Give slowly over 1 to 2 minutes.
b) PHENOBARBITAL may be used as adjunct treatment at 5 to 30 mg/kg over 5 to 10 minutes IV.
c) REFRACTORY SEIZURES: Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 mg/kg IV slowly to effect. The dose may need to be repeated in 4 to 8 hours. Be sure to protect the airway.

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

References

General Bibliography

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FeedBack

FLUOXETINE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Hematologic

Dermatologic

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Physical Characteristics

Molecular Weight

Clinical Effects

Treatment

Continuing Care

General Bibliography