Reconcile

345.79

345.110718

260-101-2

758685|714457

DTXSID7020635

White to off-white crystalline solid

QN06AB03

2922299090

21.3

white

158.4-158.9 °C

9℃

soluble in dimethylsulfoxide and water.

Store at RT

III

6.1(b)

3249

3

22-38-41-50

26-36/37/39-61-39

UI4050000

Xn,N

P273-P280-P305 + P351 + P338

H302-H318-H400

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fluoxetine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Benfield P et al; Drugs 32 (6): 481-508 (1986). Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness.|Rickels K, Schweizer E; J Clin Psychiatry 51 (Suppl B): 9-12 (1990). Clinical overview of serotonin reuptake inhibitors.

|Danger|H302 (98.02%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P273, P280, P301+P312, P302+P352, P305+P351+P338, P310, P321, P330, P332+P313, P362, P391, and P501|Aggregated GHS information provided by 101 companies from 9 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H302 (98.4%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P261, P264, P270, P271, P273, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P308+P313, P310, P312, P322, P330, P363, P391, P405, and P501|Aggregated GHS information provided by 126 companies from 17 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

IDENTIFICATION: Fluoxetine is a selective serotonin reuptake inhibitor used as an antidepressant agent. It is soluble in: water, methanol, chloroform and insoluble in hexane, ethyl acetate and benzene. HUMAN EXPOSURE: Main risks and target organs: Fluoxetine is safer in overdose than most other classes of antidepressants. In overdosage, most patients experience only mild neurological and gastroenterological symptoms; significant cardiovascular toxicity is unusual. The serotonergic effects of fluoxetine may be enhanced by combination with other antidepressants, monoamine oxidase inhibitors, carbamazepine or lithium and produce a life-threatening serotoninergic syndrome comprising hyperthermia, tremor and convulsions. Summary of clinical effects: Drowsiness, tremor, headache, blurred vision, dizziness, restlessness, and rarely, seizures and coma. Nausea, vomiting, abdominal pain. Bradycardia, mild hypertension or hypotension. Contraindications: Absolute: Hypersensitivity to fluoxetine. Coadministration of sumatriptan, non-specific monoamine oxidase inhibitors and B-specific monoamine oxidase inhibitors. Relative: Combination therapy with A-specific monoamine oxidase inhibitors or other antidepressants. Pregnancy or lactation. Routes of entry: Oral: Fluoxetine is administered orally. Absorption by route of exposure: Fluoxetine hydrochloride is readily absorbed from the gastrointestinal tract with peak plasma concentrations appearing from 6 to 8 hours after oral administration. The systemic bioavailability is greater than 85 % and does not appear to be affected by food. Distribution by route of exposure: Fluoxetine is widely distributed throughout the body. Plasma protein binding is 94 %. Biological half-life by route of exposure: Fluoxetine has a relatively long and highly variable half-life ranging from 1 to 4 days after a single dose and averaging nearly 70 hours; patients receiving high doses over long periods of time may exhibit prolonged elimination half-lives. The half-life of its active metabolite, norfluoxetine, is about 7 to 9 days. Metabolism: Fluoxetine is extensively metabolized in the liver to a desmethyl metabolite, norfluoxetine, which has activity similar to fluoxetine. Peak plasma concentrations of the active metabolite, norfluoxetine, occur around 76 hours after ingestion. Elimination and excretion: The primary route of elimination appears to be further hepatic metabolism to inactive metabolites which are conjugated and then excreted in the urine. Mode of action: Toxicodynamics: Fluoxetine is a potent inhibitor of serotonin re-uptake by Central Nervous System neurones and may interact with other drugs or circumstances which cause serotonin release. The enhancement of the serotonergic effects may produce a life-threatening serotonin syndrome. Pharmacodynamics: Fluoxetine specifically inhibits neuronal re-uptake of serotonin, thus increasing the concentration of the serotonin at the synapse and reinforcing of serotonergic neuronal transmission. Fluoxetine has little effect on other neurotransmitters. Fluoxetine has no direct effect on the heart. Carcinogenicity: Human studies: there is no evidence of carcinogenicity in patients taking fluoxetine. Teratogenicity: Human studies: a study of 128 women exposed to fluoxetine during the first trimester showed no increase in major fetal malformations. It is not known, however, if the drug is a human teratogen. A neonate whose mother had been taking fluoxetine during most of her pregnancy suffered tachypnea, emesis, continuous crying, irritability, tremor and increased muscle tone; the symptoms resolved within 96 hours. Fluoxetine and norfluoxetine are excreted in breast milk. The effects on the infant are uncertain. Caution should be exercised when fluoxetine is administered to a nursing mother. Interactions: Drug interactions with fluoxetine have been reported with L-tryptophan, L-dopa; monoamine oxidase inhibitors: selegiline, tranylcypromine; tricyclic antidepressants; selective serotonin re-uptake inhibitors: trazodone, zimeldine; benzodiazepines: alprazolam, diazepam; buspirone, lithium, anticonvulsants: carbamazepine, phenytoin, valproate; pentazocine, dextromethorphan, fenfluramine, calcium channel blockers, benztropine, cyproheptadine, clarithromycin. Cannabis, ethanol and LSD. At least 14 days should elapse between discontinuing a MAO-inhibiting antidepressant and introducing fluoxetine. Conversely, because of the long half-life of fluoxetine and its metabolite, norfluoxetine, it is recommended that at least 5 weeks should elapse between discontinuation of fluoxetine and the introduction of a MAO inhibitor. Main adverse effects: The major adverse effects reported with therapeutic doses of fluoxetine are primarily those of headache, insomnia, nausea, and nervousness. Less common adverse effects include tremors, sweating, dry mouth, anxiety, drowsiness, and diarrhea. ANIMAL/PLANT STUDIES: Carcinogenicity: Animal studies: fluoxetine was not carcinogenic in rats and mice at doses ten times the recommended daily dose for 24 months. Teratogenicity: Animal studies: in rats, fluoxetine and norfluoxetine cross the placenta and distribute within the fetus during the periods of organogenesis and postorganogenesis. Levels in fetal tissue are approximately half the corresponding maternal concentrations. Fluoxetine does not impair the fetal growth in rats or rabbits at doses nine and eleven times the maximum daily human dose respectively. Mutagenicity: In vitro: fluoxetine and norfluoxetine did not show mutagenicity in the Ames test. There was no induction of sister-chromatid exchange in the bone marrow of the Chinese Hamster.

Elevated plasma phenytoin concentrations resulting in symptoms of toxicity have been reported when fluoxetine was used concurrently with phenytoin; caution and close monitoring are suggested.|Because of the possibility that fluoxetine may inhibit the metabolism of astemizole, leading to increased blood levels and risk of cardiac arrhythmias, including torsades de pointes, concurrent use is not recommended.|Both increased and decreased lithium concentrations, as well as some cases of lithium toxicity, have been reported with concomitant fluoxetine use; close monitoring of lithium concentrations is recommended.|Concurrent use of fluoxetine with monamine oxidase (MAO) inhibitors may result in confusion, agitation, restlessness, gastrointestinal symptoms, hyperpyretic episodes, severe convulsion, hypertensive crises, the serotonin syndrome, or death. Concurrent use is contraindicated, and at least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of fluoxetine. However, because of the long half-lives of fluoxetine and its active metabolite, at least 5 weeks (approximately 5 half-lives of norfluoxetine) should elapse between discontinuation of fluoxetine and initiation of therapy with an MAO inhibitor. Deaths following the initiation of an MAO inhibitor shortly after stopping fluoxetine administration have been reported.|For more Interactions (Complete) data for FLUOXETINE HYDROCHLORIDE (19 total), please visit the HSDB record page.

LD50 Rat oral 452 mg/kg|LD50 Mouse oral 248 mg/kg

Fluoxetine and norfluoxetine are distributed into milk. Limited data indicate that concentrations of the drug and this metabolite in milk are about 20-30% of concurrent plasma concentrations.|To characterize milk/plasma (M/P) ratio and infant dose, for fluoxetine and norfluoxetine, in breast-feeding women taking fluoxetine for the treatment of depression, and to determine the plasma concentration of these drugs in their infants. Fourteen women (mean age 32.2 years) taking fluoxetine (mean dose 0.51 mg/kg/day) and their infants (mean age 3.4 months) were studied. Fluoxetine and norfluoxetine in plasma and milk were measured by high-performance liquid chromatography over a 24 hr dose interval in four patients, and by single point data collection in 10 patients. Infant exposure was estimated as the product of estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/P values of 0.68 (95% CI 0.52-0.84) and 0.56 (95% CI 0.35-0.77) were calculated for fluoxetine and norfluoxetine, respectively. Mean total infant exposure (fluoxetine equivalents) was estimated to be 6.81% (range 2.15-12%) of the weight-adjusted maternal dose of fluoxetine. Contributions from fluoxetine and norfluoxetine were approximately equal.

Fluoxetine (range 20-252 ug/L) was detected in five of the nine infants from whom /plasma/ samples were collected, and norfluoxetine (range 17-187 ug/L) was detected in seven of the nine infants. Mothers of these infants were being treated with fluoxetine for depression. The highest of these concentrations was about 70% of the maternal plasma concentrations. The mean combined dose of fluoxetine and norfluoxetine transmitted to infants via breast milk is below the 10% national level of concern. However, there was considerable interpatient variability in estimated infant dose and in some of the patients, the dose was >10%. Further, since adverse effects have been observed in breast-fed infants, careful monitoring of the infants is mandatory. Neonates exposed to these drugs in utero had higher concentrations of fluoxetine and norfluoxetine and are at greater risk of adverse effects.

As an aid in the treatment of separation-related disorders in dogs manifested by destruction and inappropriate behaviours (vocalisation and inappropriate defecation and / or urination) and only in combination with behavioural-modification techniques.

Antidepressive Agents, Second-Generation; Serotonin Uptake Inhibitors|Fluoxetine is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder. /Included in US product labeling/|Fluoxetine is used to relieve the symptoms of premenstrual dysphoric disorder (PMDD). PMDD was formerly known as late luteal phase dysphoric disorder (LLPDD) and is distinguishable from the cyclic changes in mood commonly known as premenstrual syndrome (PMS) by its greater severity of symptoms. (Evidence rating: B-1) /Included in US product labeling/|Fluoxetine is indicated for the treatment of major depressive disorder. Treatment of acute depressive episodes typically requires 6 to 12 months of antidepressant therapy. Patients with recurrent or chronic depression may require long-term treatment. Fluoxetine has shown effective maintenance of antidepressant response for up to 50 weeks of treatment in a placebo-controlled trial. /Included in US product labeling/|For more Therapeutic Uses (Complete) data for FLUOXETINE HYDROCHLORIDE (10 total), please visit the HSDB record page.

Pregnancy risk category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./|Fluoxetine potentially may alter blood glucose concentrations. Hypoglycemia has occurred in less than 1% of patients receiving fluoxetine and hypoglycemic reaction has occurred rarely. In addition, hyperglycemia has developed following discontinuance of the drug. Therefore, the possibility that insulin and/or oral sulfonylurea antidiabetic agent dosage adjustments may be necessary when fluoxetine therapy is initiated or discontinued in patients with diabetes mellitus should be considered.|The most frequent adverse effect associated with fluoxetine therapy is nausea, which occurs in about 21% of patients. Nausea generally is mild, occurs early in therapy, and usually subsides after a few weeks of continued therapy with the drug. ... Diarrhea occurs in about 12%, anorexia in about 9%, and dyspepsia in about 6% of patients receiving the drug; limited evidence suggests that the incidence of anorexia may be dose-related. Other adverse GI effects associated with fluoxetine therapy include abdominal pain and change in taste perception, which occur in approximately 3 and 2% of patients, respectively; taste loss has been reported rarely. Vomiting, melena, and flatulence reportedly occur in about 2% and gastroenteritis in about 1% of patients receiving the drug. Increased appetite has been reported in more than 1% of patients receiving fluoxetine, but has not been definitely attributed to the drug. Other adverse GI effects, including aphthous stomatitis, dysphagia, eructation, esophagitis, gastritis, gingivitis, glossitis, melena, stomatitis, and thirst, have been reported in less than 1% of fluoxetine-treated patients; however, a causal relationship to the drug has not been established. Bloody diarrhea, colitis, duodenal or gastric ulcer, enteritis, fecal incontinence, hematemesis, hyperchlorhydria, increased salivation, mouth ulceration, salivary gland enlargement, tongue discoloration, and tongue edema have occurred rarely, but have not been definitely attributed to fluoxetine.|Because of the possibility of suicide in depressed patients, close supervision of high risk patients is recommended during initial fluoxetine therapy. To reduce the risk of overdosage, the drug should be prescribed in the smallest quantity consistent with good patient management. Suicidal ideation may persist until substantial remission of the depressive disorder occurs.|For more Drug Warnings (Complete) data for FLUOXETINE HYDROCHLORIDE (14 total), please visit the HSDB record page.

A structurally and mechanistically diverse group of drugs that are not tricyclics or monoamine oxidase inhibitors. The most clinically important appear to act selectively on serotonergic systems, especially by inhibiting serotonin reuptake. (See all compounds classified as Antidepressive Agents, Second-Generation.)|Compounds that specifically inhibit the reuptake of serotonin in the brain. (See all compounds classified as Serotonin Uptake Inhibitors.)|Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2D6. (See all compounds classified as Cytochrome P-450 CYP2D6 Inhibitors.)

Fluoxetine hydrochloride appears to be well absorbed from the GI tract following oral administration. The oral bioavailability of fluoxetine in humans has not been fully elucidated to date, but at least 60-80% of an oral dose appears to be absorbed. However, the relative proportion of an oral dose reaching systemic circulation unchanged currently is not known. Limited data from animals suggest that the drug may undergo first-pass metabolism and extraction in the liver and/or lung following oral administration. In these animals (beagles), approximately 72% of an oral dose reached systemic circulation unchanged. Food appears to cause a slight decrease in the rate, but not the extent of absorption of fluoxetine in humans.|Distribution of fluoxetine and its metabolites into human body tissues and fluids has not been fully characterized. Limited pharmacokinetic data obtained during long term administration of fluoxetine to animals suggest that the drug and some of its metabolites, including norfluoxetine, are widely distributed in body tissues, with highest concentrations occurring in the lungs and liver. The drug crosses the blood-brain barrier in humans and animals. In animals, fluoxetine: norfluoxetine ratios reportedly were similar in the cerebral cortex, corpus striatum, hippocampus, hypothalamus, brain stem, and cerebellum 1 hr after administration of single dose of the drug.|In order to confirm embryonic/fetal exposure to fluoxetine and/or metabolites, dissection and whole-body autoradiographic techniques were utilized to determine the placental transfer and fetal distribution in 12 and 18 day pregnant Wistar rats 1, 4, 8, and 24 hr following a single oral 12.5 mg/kg dose of (14)C fluoxetine. On gestation Days 12 (organogenesis) and 18 (postorganogenesis), peak concentrations of radiocarbon occurred 4-8 hr after dose administration in the placenta, embryo/fetus, amniotic fluid, and maternal kidney, brain, and lung, and declined slightly at 24 hr postdose. Maternal lung contained the highest tissue concentration of radiocarbon at all time points. Placenta and maternal brain, kidney, and liver contained moderate levels of radioactivity, while embryonic/fetal tissue, amniotic fluid, and maternal plasma contained low levels of radioactivity. Mean fetal concentrations of radiocarbon at 4, 8, and 24 hr on gestation Day 18 were higher than mean embryonic concentrations on Day 12 of gestation. Analytical characterization of radioactivity indicated that combined fluoxetine and norfluoxetine concentrations accounted for 63-80% of the total radiocarbon concentrations in embryonic/fetal tissue. Results indicated that embryonic/fetal and maternal tissue levels of fluoxetine were greatest at early time points and declined with time, while norfluoxetine tissue levels were highest at the 24 hr time point. Whole-body autoradiographic techniques demonstrated that radioactivity associated with (14)C fluoxetine and/or its metabolites traversed the placenta and distributed throughout the 18 day fetus 4 hr following dose administration. Visual and quantitative evaluations of the autoradiograms indicated that the highest fetal concentrations of radiocarbon were associated with brain and thymus. Results from these studies indicate that fluoxetine and norfluoxetine traverse the placenta and distribute within the embryo/fetus during the periods of organogenesis and postorganogenesis and confirm embryonic/fetal exposure of parent and metabolite in previous negative rat teratology and reproductive studies.|Elimination: Renal: 80% excreted in the urine (11.6% fluoxetine, 7.4% fluoxetine glucuronide, 6.8% norfluoxetine, 8.2% norfluoxetine glucuronide, >20% hippuric acid, 46% other); Biliary: Approximately 15% in the feces; In dialysis--Not dialyzable because of high protein binding and large volume of distribution.|For more Absorption, Distribution and Excretion (Complete) data for FLUOXETINE HYDROCHLORIDE (6 total), please visit the HSDB record page.

The present study was designed to define the kinetic behavior of fluoxetine N-demethylation in human liver microsomes and to identify the isoforms of cytochrome p450 (CYP) involved in this metabolic pathway. The kinetics of Ne formation of norfluoxetine was determined in human liver microsomes from six genotyped CYP2C19 extensive metabolizers (EM). The correlation studies between the fluoxetine N-demethylase activity and various CYP enzyme activities were performed. Selective inhibitors or chemical probes of various cytochrome P-450 isoforms were also employed. The kinetics of norfluoxetine formation in all liver microsomes were fitted by a single-enzyme Michaelis-Menten equation (mean Km=32 umol/L +/- 7 umol/L). Significant correlations were found between N-demethylation of fluoxetine at both 25 umol/L and 100 umol/L and 3-hydroxylation of tolbutamide at 250 micromol/L (r1=0.821, P1=0.001; r2=0.668, P2=0.013), respectively, and S-mephenytoin 4'-hydroxylase activity (r=0.717, P=0.006) at high substrate concentration of 100 umol/L. S-mephenytoin (SMP) (a CYP2C19 substrate) at high concentration and sulfaphenazole (SUL) (a selective inhibitor of CYP2C9) substantially inhibited norfluoxetine formation. The reaction was minimally inhibited by coincubation with chemical probe, inhibitor of CYP3A4 (triacetyloleandomycin, TAO). The inhibition of fluoxetine N-demethylation at high substrate concentration (100 umol/L) was greater in PM livers than in EM livers (73 % vs 45 %, P < 0.01) when the microsomes were precoincubated with SUL plus TAO. Cytochrome p450 CYP2C9 is likely to be a major CYP isoform catalyzing fluoxetine N-demethylation in human liver microsomes at a substrate concentration close to the therapeutic level, while polymorphic CYP2C19 may play a more important role in this metabolic pathway at high substrate concentration.|The exact metabolic fate of fluoxetine has not been fully elucidated. The drug appears to be metabolized extensively, probably in the liver, to norfluoxetine and several other metabolites. Norfluoxetine (desmethylfluoxetine) the principal metabolite, is formed by N-demethylation of fluoxetine, which may be under polygenic control. The potency and selectivity of norfluoxetine's serotonin-reuptake inhibiting activity appear to be similar to those of the parent drug. Both fluoxetine and norfluoxetine undergo conjugation with glucuronic acid in the liver, and limited evidence from animals suggests that both the parent drug and its principal metabolite also undergo O-dealkylation to form p-trifluoromethylphenol, which subsequently appears to be metabolized to hippuric acid.

The half-life of fluoxetine reportedly is prolonged (to approximately 4-5 days) after administration of multiple versus single doses, suggesting a nonlinear pattern of drug accumulation during long-term administration.|Following a single oral dose of fluoxetine in healthy adults, the elimination half-life of fluoxetine reportedly averages approximately 2-3 days (range: 1-9 days) and that of norfluoxetine averages about 7-9 days (range: 3-15 days).|The mean half-life /for fluoxetine/ was 6.6 vs 2.2 days ... for patients with cirrhosis vs normal volunteers.

The precise mechanism of antidepressant action of fluoxetine is unclear, but the drug has been shown to selectively inhibit the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane. Fluoxetine-induced inhibition of serotonin reuptake causes increased synaptic concentrations of serotonin in the CNS, resulting in numerous functional changes associated with enhanced serotonergic neurotransmission.|Monoamine oxidase-B has been determined to be the enzyme responsible for the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into its toxic metabolite 1-methyl-4-phenylpyridine ion. Since this enzyme has been localized primarily in astrocytes and serotonergic neurons, it would appear that 1-methyl-4-phenylpyridine ion is being produced outside the dopaminergic neurons. To investigate this possibility, the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was preceded by systemically administered fluoxetine. In keeping with its demonstrated ability to inhibit uptake into serotonergic neurons and serotonin uptake into astrocytes, fluoxetine pretreatment resulted in a significant attenuation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced depletions of striatal dopamine and serotonin concentration. These results support the extra-dopaminergic production of 1-methyl-4-phenylpyridine ion.|Fluoxetine is a potent and selective inhibitor of the neuronal serotonin-uptake carrier and is a clinically effective antidepressant. Although fluoxetine is used therapeutically as the racemate, there appears to be a small but demonstrable stereospecificity associated with its interactions with the serotonin-uptake carrier. The goals of this study were to determine the absolute configurations of the enantiomers of fluoxetine and to examine whether the actions of fluoxetine in behavioral tests were enantiospecific. (S)-Fluoxetine was synthesized from (S)-(-)-3-chloro-1-phenylpropanol by sequential reaction with sodium iodide, methylamine, sodium hydride, and 4-fluorobenzotrifluoride. (S)-Fluoxetine is dextrorotatory (+1.60) in methanol, but is levorotatory (-10.85) in water. Fluoxetine enantiomers were derivatized with (R)-1-(1-naphthyl)ethyl isocyanate, and the resulting ureas were assayed by 1H NMR or HPLC to determine optical purities of the fluoxetine samples. Both enantiomers antagonized writhing in mice; following sc administration of (R)- and (S)-fluoxetine, ED50 values were 15.3 and 25.7 mg/kg, respectively. Moreover, both enantiomers potentiated a subthreshold analgesic dose (0.25 mg/kg) of morphine, and ED50 values were 3.6 and 5.7 mg/kg, respectively. Following ip administration to mice, the two stereoisomers antagonized p-chloroamphetamine-induced depletion of whole brain serotonin concentrations. ED50 values for (S)- and (R)-fluoxetine were 1.2 and 2.1 mg/kg, respectively. The two enantiomers decreased palatability-induced ingestion following ip administration to rats; (R)- and (S)-fluoxetine reduced saccharin-induced drinking with ED50 values of 6.1 and 4.9 mg/kg, respectively. Thus, in all biochemical and pharmacological studies to date, the eudismic ratio for the fluoxetine enantiomers is near unity.

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/|Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat hypertension, hypotension, coma, seizures, and hyperthermia if they occur. Continuously monitor temperature, other vital signs, and ECG for a minimum of 6 hours in asymptomatic patient, and admit all symptomatic patients for continuous monitoring for 24 hours. Since the hypertension is catecholamine-mediated, alpha-adrenergic blockers (e.g., phentolamine) or combined alpha- and beta-adrenergic blockers (e.g., labetalol) are particularly useful. /MAO Inhibitors/|For suspected serotonin syndrome, anecdotal reports claim benefit from cyproheptadine (periactin), ... orally every hour for 3 doses, or methysergide (Sansert), ... orally every 6 hours for 3 doses, presumably because of the serotonin antagonist effects of these drugs. /Serotonin syndrome/|...In this descriptive case series, five cases of serotonin syndrome are reported. All patients gave a history of recent exposure to one or more serotonergic medications, including moclobemide, paroxetine, sertraline, and venlafaxine, with clinical evidence of serotonin syndrome. All patients were administered cyproheptadine (4-8 mg orally) for serotonergic signs. Three had complete resolution of signs within 2 hr of administration. Another two had a residual tremor or hyperreflexia following the first dose, which resolved following a repeat dose. There were no adverse outcomes from cyproheptadine use. The role of specific serotonin receptor antagonists such as cyproheptadine in the treatment of the serotonin syndrome remains to be delineated. Its use should be considered an adjunct to supportive care. Currently, it is unknown whether cyproheptadine modifies patient outcome.

/SIGNS AND SYMPTOMS/ In general, overdosage of fluoxetine may be expected to produce effects that are extensions of the drug's pharmacologic and adverse effects. Animal studies and case reports in humans indicate that possible effects of overdosage include agitation, restlessness, hypomania, insomnia, tremor, and other signs of CNS excitation; nausea and vomiting; and tachycardia and/or increased blood pressure.|/CASE REPORTS/ To report the development of a possible serotonin syndrome in a patient taking buspirone and fluoxetine. A 37-year-old white man taking fluoxetine 20 mg/d for generalized anxiety disorder developed confusion, diaphoresis, incoordination, diarrhea, and myoclonus after buspirone was added to the drug regimen. Serotonin syndrome is a potentially lethal condition of serotonin hyperstimulation, which may develop rapidly or over the course of several weeks. Symptoms of serotonin syndrome typically occur following additions or increases of serotonin-enhancing drugs. Although buspirone has variable effects on post- and presynaptic 5-HT1A receptors that may reduce the risk of serotonin syndrome when administered as a single agent, it may cause an adverse reaction when given with other serotonergic drugs. Symptoms consistent with serotonin syndrome may develop with the concurrent administration of buspirone and fluoxetine.|/CASE REPORTS/ A possible case of serotonin syndrome in a 45 yr old depressed woman resulting from the administration of 20-40 mg/day of fluoxetine hydrochloride (Prozac), 10-20 mg 2 times/day of tranylcypromine sulfate (Parnate), and 500 mg/day of tryptophan to treat refractory depression is described. It was likely that the combination of prozac, parnate, and tryptophan increased the availability of serotonin in the CNS to produce the syndrome. The patient died and the cause of death was listed as toxic encephalopathy with multisystem failure caused by neuroleptic malignant syndrome.|/CASE REPORTS/ Self-injurious ideation or behavior appeared de novo or intensified during fluoxetine treatment of obsessive-compulsive disorder in six patients, age 10-17 yr old, who were among 42 young patients receiving fluoxetine for obsessive-compulsive disorder at a university clinical research center. These symptoms required the hospitalization of four patients. Before receiving fluoxetine, four patients had major risk factors for self-destructive behavior including depression or prior suicidal ideation or self-injury.|For more Human Toxicity Excerpts (Complete) data for FLUOXETINE HYDROCHLORIDE (11 total), please visit the HSDB record page.

Fluoxetin

Oral: Capsules: 10 mg (of fluoxetine), Prozac Pulvules (Dista), Sarafem Pulvules (Lilly); 20 mg (of fluoxetine), Prozac Pulvules (Dista), Sarafem Pulvules (Lilly); 40 mg (of fluoxetine), Prozac Pulvules (Dista). Capsules, delayed-release (containing enteric-coated pellets): 90 mg (of Fluoxetine) Prozac Weekly (Dista). Solution: 20 mg (of fluoxetine) per 5 ml, Prozac (with alcohol 0.23%) (Dista). Tablets: 10 mg (of fluoxetine) Prozac (scored) (Dista); 20 mg (of fluoxetine), Fluoxetine Hydrochloride Tablets (Par).

Commercially available as the hydrochloride salt.|(S)-Fluoxetine was synthesized from (S)-(-)-3-chloro-1-phenylpropanol by sequential reaction with sodium iodide, methylamine, sodium hydride, and 4-fluorobenzotrifluoride, (S)-Fluoxetine is dextrorotatory (+1.60) in methanol, but is levorotatory (-10.85) in water.|Preparation: ...B. B. Malloy, K. K. Schmiegel, DE 2500110; B. B. Malloy, K. K. Schmiegel, US 4314081 (1975, 1982 both to Lilly)

A rapid, selective, and sensitive method is described for the purification and analysis of fluoxetine and norfluoxetine using a solid phase extraction column and GC with ECD /electron capture detection. Linear quant response curves for fluoxetine and norfluoxetine are generated over a concn range of 20-200 ng/ml. Overall extraction efficiency of the extraction procedure is found to be >90% and >75% with correlation coefficients of 0.997 and 0.993 for fluoxetine and norfluoxetine, respectively.|Analyte: fluoxetine hydrochloride; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: fluoxetine hydrochloride; matrix: chemical identification; procedure: visual reaction (white, curdy precipitate) with silver nitrate (Chloride test)|Analyte: fluoxetine hydrochloride; matrix: chemical purity; procedure: liquid chromatography with detection at 227 nm and comparison to standards|For more Analytic Laboratory Methods (Complete) data for FLUOXETINE HYDROCHLORIDE (10 total), please visit the HSDB record page.

A reversed phase liquid chromatog procedure with fluorescence detection for the simultaneous determination of fluoxetine and its active metabolite, norfluoxetine in human serum is described. A 0.5 ml aliquot of the sample after the addition of protriptyline as the internal std is passed through a 1 ml BondElut C18 silica extraction column. The column is selectively washed to remove polar, neutral, acidic and weakly basic cmpd. The desired cmpd are eluted with a 0.25 ml aliquot of a mixture of 0.1 N perchloric acid + acetonitrile (1:3). A 20 ul aliquot of the elute is injected onto a column packed with 5 um C8-silica particles, which is eluted at ambient temp with a mobile phase containing tetramethylammonium perchlorate. The peaks are detected with a fluorescence detector (ex= 235 nm; em= 310 nm). In the resulting chromatogram, there are only a few extraneous peaks fluoxetines give sharp peaks which are well resolved from peaks for solvent and internal std. The extraction recovery of fluoxetines and internal std is in the range of 85%.|An HPLC assay was developed for a recently introduced atypical antidepressant, fluoxetine and its demethylated metabolite, norfluoxetine. Prior to analysis, aliquots of alkalinized plasma were extracted with n-hexane and isoamyl alcohol, followed by back-extraction with diluted phosphoric acid. These extracts were injected into a 10 um, reversed-phase C18 column with phosphate and acetonitrile as the mobile phase and detection at 214 nm. Peak height ratios were linearly correlated up to 800 ug/L. Acceptable coefficients of variation were demonstrated for both within-run and day-to-day studies. Selected drugs were checked for interference. The assay was used to monitor 9 patients receiving 20 to 80 mg of fluoxetine/day. Plasma concns of fluoxetine and norfluoxetine ranged from 37 to 301 ug/L and 29 to 326 ugLl respectively.|The GC method for assay of fluoxetine and norfluoxetine in human plasma involves extraction of the drugs and use of a (63)Ni ECD. The organ/methane carrier gas flow was 40 mL/min. The injector, detector, and column temps were 250, 300, and 190 °C, respectively. The linear range of detection is 25 to 800 ug/L for each drug. Overall precision in the concn range of 10 to 100 ug/L for both drugs was approx 10%. Accuracy (relative error) in the same concn range was approx +10%. None of the commonly prescribed antidepressants or tranquilizers interfered with the assay.|Basic drugs were routinely extracted from whole blood under alk conditions into butyl acetate. The extract was injected into a gas chromatog with a N-P detector and a wide-bore cross-linked 50% PhMe silicone capillary column. Absolute and relative retention times were recorded for >100 extracted drug stds. Recovery from the whole blood was determined for some of the more frequently encountered drugs. This 1-step extraction is reliable for general screening and was used routinely in forensic and clinical toxicol analyses.|A procedure has been developed for measuring fluoxetine and its desmethyl metabolite, norfluoxetine, in serum by reversed-phase HPLC with UV detection at 226 nm. Fluoxetine and norfluoxetine are isolated from serum by liq-liq extraction. They are then separated by HPLC and quantified, with reduced haloperidol as the internal std. Fluoxetine, norfluoxetine, and the reduced haloperidol are separated from all interfering peaks in about 15 min. The std curve is linear for both fluoxetine and norfluoxetine concns over the range of 25 to 800 ug/L. Between-run relative std deviations for 60 and 200 ug/L controls were 6.8 and 4.1% for fluoxetine, and 8.8 and 6.2% for norfluoxetine, respectively. In a study of 24 patients with depression who were being treated with 20-60 mg of fluoxetine per day, fluoxetine and norfluoxetine concns. in serum, measured during the last three weeks of treatment, were 47-469 ug/L and 52-446 ug/L, respectively.

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