Fluoxetine

309.33

309.33

244-296-1

283480

DTXSID7023067

QN06AB03|N06AB03|N - Nervous system

29036990

21.3

4.6

Solid

1.2±0.1 g/cm3

158 °C

395.1±42.0 °C at 760 mmHg

192.8±27.9 °C

1.511

1.70e-03 g/L

Keep in a cool, dry, dark location in a tightly sealed container or cylinder. Keep away from incompatible materials, ignition sources and untrained individuals. Secure and label area. Protect containers/cylinders from physical damage.

176.5 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|174.5 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

III

8

UN 3265 8/PG 2

2

R34:Causes burns. R36/37:Irritating to eyes and respiratory system . R36/37/38:Irritating to eyes, respiratory system and skin .

S23-S26-S27-S36/37/39-S45-S37/39

C,Xi

P260, P261, P264, P270, P271, P273, P280, P284, P301+P312, P302+P352, P304+P340, P305+P351+P338, P310, P312, P314, P320, P321, P330, P332+P313, P362, P391, P403+P233, P405, P501

H302

|Danger|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P260, P261, P264, P270, P271, P273, P280, P284, P301+P312, P302+P352, P304+P340, P305+P351+P338, P310, P312, P314, P320, P321, P330, P332+P313, P362, P391, P403+P233, P405, and P501|Aggregated GHS information provided by 4 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In a report that included 234 fluoxetine overdose cases, it was concluded that symptoms resulting from fluoxetine overdose were generally minor and short in duration. The most common overdose adverse effects included drowsiness, tremor, tachycardia, nausea and vomiting, and providing the patient with aggressive supportive care was the recommended intervention. Despite this evidence, more severe adverse effects have been linked to fluoxetine ingestion although most of these reports involved co-ingestion with other substances or drugs as well as other factors. For example, there is a case report that details a patient who ingested 1400 mg of fluoxetine in a suicide attempt and as a result, experienced a generalized seizure three hours later. In a separate case, a 14 year old patient ingested 1.2 g of fluoxetine and subsequently experienced tonic/clonic seizures, symptoms consistent with serotonin syndrome, and rhabdomyolysis, although the patient did not experience sustained renal injury.

Liver test abnormalities have been reported to occur rarely in patients on fluoxetine (less than 1%), and elevations are usually modest and usually do not require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on fluoxetine. The onset of injury is usually within 2 to 12 weeks and the pattern of serum enzyme elevations is usually hepatocellular, but convincing cases of mixed and cholestatic injury have also been described. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.

Approximately 94% of fluoxetine is plasma protein bound.

Fluoxetine is indicated for both acute and maintenance treatment of major depressive disorder, obsessive compulsive disorder, and bulimia nervosa; however, it is only indicated for acute treatment of panic disorder independent of whether agoraphobia is present. Fluoxetine may also be used in combination with olanzapine to treat depression related to Bipolar I Disorder, and treatment resistant depression.|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.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) widely used as an antidepressant. Fluoxetine therapy can be associated with transient asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.

Antidepressant Agents

Fluoxetine has known transformation products that include Norfluoxetine.

Fluoxetine blocks the serotonin reuptake transporter in the presynaptic terminal, which ultimately results in sustained levels of 5-hydroxytryptamine (5-HT) in certain brain areas. However, fluoxetine binds with relatively poor affinity to 5-HT, dopaminergic, adrenergic, cholinergic, muscarinic, and histamine receptors which explains why it has a far more desirable adverse effect profile compared to earlier developed classes of antidepressants such as tricyclic antidepressants.

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.)|Compounds that specifically inhibit the reuptake of serotonin in the brain. (See all compounds classified as Serotonin Uptake Inhibitors.)|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.)

The oral bioavailability of fluoxetine is <90% as a result of hepatic first pass metabolism. In a bioequivalence study, the Cmax of fluoxetine 20 mg for the established reference formulation was 11.754 ng/mL while the Cmax for the proposed generic formulation was 11.786 ng/ml. Fluoxetine is very lipophilic and highly plasma protein bound, allowing the drug and it's active metabolite, norfluoxetine, to be distributed to the brain.|Fluoxetine is primarily eliminated in the urine.|The volume of distribution of fluoxetine and it's metabolite varies between 20 to 42 L/kg.|The clearance value of fluoxetine in healthy patients is reported to be 9.6 ml/min/kg.

Fluoxetine is metabolized to norfluoxetine by CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 upon ingestion. Although all of the mentioned enzymes contribute to N-demethylation of fluoxetine, CYP2D6, CYP2C9 and CYP3A4 appear to be the major contributing enzymes for phase I metabolism. In addition, there is evidence to suggest that CYP2C19 and CYP3A4 mediate O-dealkylation of fluoxetine and norfluoxetine to produce para-trifluoromethylphenol which is subsequently metabolized to hippuric acid. Both fluoxetine and norfluoxetine undergo glucuronidation to facilitate excretion. Notably, both the parent drug and active metabolite inhibit CYP2D6 isozymes, and as a result patients who are being treated with fluoxetine are susceptible to drug interactions.|Fluoxetine has known human metabolites that include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[methyl-[3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]amino]oxane-2-carboxylic acid, Norfluoxetine, and p-Trifluoromethyl phenol.

The half life of fluoxetine is significant with the elimination half-life of the parent drug averaging 1-3 days after acute administration, and 4-6 days after chronic administration. Further, the elimination half life of it's active metabolite, norfluoxetine, ranges from 4-16 days after both acute and chronic administration. The half-life of fluoxetine should be considered when switching patients from fluoxetine to another antidepressant since marked accumulation occurs after chronic use. Fluoxetine's long half-life may even be beneficial when discontinuing the drug since the risk of withdrawal is minimized.

The monoaminergic hypothesis of depression emerged in 1965 and linked depression with dysfunction of neurotransmitters such as noradrenaline and serotonin. Indeed, low levels of serotonin have been observed in the cerebrospinal fluid of patients diagnosed with depression. As a result of this hypothesis, drugs that modulate levels of serotonin such as fluoxetine were developed. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and as the name suggests, it exerts it's therapeutic effect by inhibiting the presynaptic reuptake of the neurotransmitter serotonin. As a result, levels of 5-hydroxytryptamine (5-HT) are increased in various parts of the brain. Further, fluoxetine has high affinity for 5-HT transporters, weak affinity for noradrenaline transporters and no affinity for dopamine transporters indicating that it is 5-HT selective. Fluoxetine interacts to a degree with the 5-HT_2C receptor and it has been suggested that through this mechanism, it is able to increase noradrenaline and dopamine levels in the prefrontal cortex.

Fluoxetin

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