DINALEXIN

Fluoxetine is a 2nd generation antidepressant categorized as a selective serotonin reuptake inhibitor (SSRI).

It gained

FDA approval in and although it was initially intended for the treatment of depression, today it is commonly prescribed to manage depression in addition to various other pathologies.

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.

Fluoxetine is additionally indicated for the treatment of female patients with premenstrual dysphoric disorder (PMDD).

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. 13 2.

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.

The volume of distribution of fluoxetine and it's metabolite varies between 20-42 L/kg.

Fluoxetine is metabolized to norfluoxetine by

CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 upon ingestion. 13 8 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. 9 10 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. 13 16 Hover over products below to view reaction partners Fluoxetine Norfluoxetine 4-Trifluoromethylphenol Hippuric acid Norfluoxetine alcohol Norfluoxetine acid Norfluoxetine glucuronide 4-Trifluoromethylphenol Hippuric acid Fluoxetine glucuronide.

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 clearance value of fluoxetine in healthy patients is reported to be 9.6 ml/min/kg.

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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. 4 5 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.

When using fluoxetine capsules and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax.

Do not use MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine.

Do not use fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders.

In addition, do not start fluoxetine in a patient who is being treated with linezolid or intravenous methylene blue Pimozide: Do not use.

Risk of QT prolongation and drug interaction Thioridazine: Do not use.

Risk of

QT interval prolongation and elevated thioridazine plasma levels.

Do not use thioridazine within 5 weeks of discontinuing fluoxetine.

Do not use thioridazine within 5 weeks of discontinuing fluoxetine When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome.

The use of fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.

Starting fluoxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome. 4.2 Other Contraindications The use of fluoxetine is contraindicated with the following: Pimozide Thioridazine Pimozide and thioridazine prolong the QT interval.

Fluoxetine can increase the levels of pimozide and thioridazine through inhibition of CYP2D6.

Fluoxetine can also prolong the

QT interval.

MDD 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) OCD 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa 60 mg/day in am Panic Disorder 10 mg/day (initial dose) Depressive Episodes Associated with Bipolar I Disorder Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) Oral in combination with olanzapine: 2.5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications Fluoxetine capsules and olanzapine in combination: Dosage adjustments should be made with the individual components according to efficacy and tolerability Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults.

Safety of the coadministration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages to 17 2.1 Major Depressive Disorder Initial Treatment Adult — Initiate fluoxetine 20 mg/day orally in the morning.

Consider a dose increase after several weeks if insufficient clinical improvement is observed.

Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon).

The maximum fluoxetine dose should not exceed 80 mg/day. In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases.

Pediatric (children and adolescents) — Initiate Fluoxetine 10 or 20 mg/day. After 1 week at 10 mg/day, increase the dose to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. Consider a dose increase to 20 mg/day after several weeks if insufficient clinical improvement is observed.

In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of to 20 mg/day.

All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer.

Periodically reassess to determine the need for maintenance treatment.

Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. 2.2 Obsessive Compulsive Disorder Initial Treatment Adult — Initiate fluoxetine 20 mg/day, orally in the morning.

The full therapeutic effect may be delayed until 5 weeks of treatment or longer.

A dose range of to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD.

The maximum fluoxetine dose should not exceed 80 mg/day. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo.

In one of these studies, no dose-response relationship for effectiveness was demonstrated.

Pediatric (children and adolescents) — In adolescents and higher weight children, initiate treatment with a dose of 10 mg/day. After 2 weeks, increase the dose to 20 mg/day. Consider additional dose increases after several more weeks if insufficient clinical improvement is observed.

A dose range of to 60 mg/day is recommended.

In lower weight children, initiate treatment with a dose of 10 mg/day. Consider additional dose increases after several more weeks if insufficient clinical improvement is observed.

A dose range of to 30 mg/day is recommended.

Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of to 60 mg/day.

Periodically reassess to determine the need for treatment. 2.3 Bulimia Nervosa Initial Treatment — Administer fluoxetine 60 mg/day in the morning.

For some patients it may be advisable to titrate up to this target dose over several days.

Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia.

In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo.

Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting.

Periodically reassess to determine the need for maintenance treatment. 2.4 Panic Disorder Initial Treatment — Initiate treatment with fluoxetine 10 mg/day. After one week, increase the dose to 20 mg/day. Consider a dose increase after several weeks if no clinical improvement is observed.

Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder.

In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of to 60 mg/day.

The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. Periodically reassess to determine the need for continued treatment. 2.5 Fluoxetine and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

Adult — Administer fluoxetine in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine.

Make dosage adjustments, if indicated, according to efficacy and tolerability within dose ranges of fluoxetine to 50 mg and oral olanzapine to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine to 12 mg and fluoxetine to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Periodically re-examine the need for continued pharmacotherapy.

Children and adolescents (10-17 years of age) — Administer olanzapine and fluoxetine combination once daily in the evening, generally beginning with 2.5 mg of olanzapine and 20 mg of fluoxetine.

Make dosage adjustments, if indicated, according to efficacy and tolerability.

Safety of co-administration of doses above 12 mg of olanzapine with 50 mg of fluoxetine has not been evaluated in pediatric clinical studies.

Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine).

Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax.

Adjust dosage, if indicated, with the individual components according to efficacy and tolerability.

Table 1: Approximate Dose Correspondence Between Symbyax and the Combination of Fluoxetine and Olanzapine For Symbyax (mg/day) Use in Combination Olanzapine (mg/day) Fluoxetine (mg/day) 1 Symbyax (olanzapine/fluoxetine HCL) is a fixed-dose combination of fluoxetine and olanzapine. 3 mg olanzapine/25 mg fluoxetine 2.5 20 6 mg olanzapine/25 mg fluoxetine 5 20 12 mg olanzapine/25 mg fluoxetine 10+2.5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2.5 40+10 Fluoxetine capsules monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. 2.7 Dosing in Specific Populations Treatment of Pregnant Women — When treating pregnant women with fluoxetine, the physician should carefully consider the potential risks and potential benefits of treatment.

Neonates exposed to SSRIs or

SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.

Geriatric — Consider a lower or less frequent dosage for the elderly.

Impairment — As with many other medications, use a lower or less frequent dosage in patients with hepatic impairment.

Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments.

Fluoxetine capsules and Olanzapine in

Combination — Use a starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, non-smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine.

Titrate slowly and adjust dosage as needed in patients who exhibit a combination of factors that may slow metabolism.

Fluoxetine and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 10 years of age. 2.8 Discontinuation of Treatment Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported. 2.9 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric.

Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluoxetine.

Conversely, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI intended to treat psychiatric disorders. 2.10 Use of Fluoxetine with Other MAOIs such as Linezolid or Methylene Blue Do not start fluoxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome.

In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.

In some cases, a patient already receiving fluoxetine therapy may require urgent treatment with linezolid or intravenous methylene blue.

If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linez.

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C — Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure.

Treatment of Pregnant Women during the First Trimester — There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women.

Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results.

More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall.

However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1,359) who were not exposed to fluoxetine.

There was no specific pattern of cardiovascular malformations.

Overall, however, a causal relationship has not been established.

Effects — Neonates exposed to fluoxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.

Such complications can arise immediately upon delivery.

Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.

These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome.

It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.

Infants exposed to

SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN).

PPHN occurs in to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality.

Several recent epidemiological studies suggest a positive statistical association between SSRI use (including fluoxetine) in pregnancy and PPHN.

Other studies do not show a significant statistical association.

Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission.

Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.

When treating a pregnant woman with fluoxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant.

The decision can only be made on a case by case basis.

Data — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m 2 basis) throughout organogenesis.

However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m 2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m 2 basis) during gestation and lactation.

There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation.

The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m 2 basis).

Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.

In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL.

The concentration in the mother’s plasma was 295.0 ng/mL.

No adverse effects on the infant were reported.

In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools.

The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.

Use of fluoxetin e in children.

• The efficacy of fluoxetine for the treatment of Major Depressive Disorder was demonstrated in two 8.

• to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages to ≤18.

The efficacy of fluoxetine for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages to <18.

The safety and effectiveness in pediatric patients <8 years of age in Major Depressive Disorder and <7 years of age in OCD have not been established.

Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages to ≤18) with Major Depressive Disorder or OCD.

The acute adverse reaction profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine.

The longer-term adverse reaction profile observed in the 19-week Major Depressive Disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine.

Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients.

Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined.

Consequently, regular monitoring for the occurrence of mania/hypomania is recommended.

As with other

SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients.

After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo.

In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels.

The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration.

In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients.

Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine.

Fluoxetine is approved for use in pediatric patients with MDD and OCD.

Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need.

• Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity.

Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day), increased serum levels of creatine kinase (at AUC as low as to 2 times the average AUC in pediatric patients at the MRHD of 20 mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at AUC to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day).

The high dose of 30 mg/kg/day exceeded a maximum tolerated dose.

When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1 to 0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose).

In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible.

The reversibility of fluoxetine-induced muscle damage was not assessed.

These fluoxetine toxicities in juvenile rats have not been observed in adult animals.

Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1 to 0.2, 1 to 2, and to 10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, are approximately 0.3 to 0.8, 1 to 8, and to 20 times, respectively, the pediatric exposure at the MRHD.

A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on mg/m 2 basis.

There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected.

Use of fluoxetine in combination with olanzapine in children and adolescents: Safety and efficacy of fluoxetine and olanzapine in combination in patients to 17 years of age have been established for the acute treatment of depressive episodes associated with Bipolar I Disorder.

Safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 10 years of age have not been established.

US fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years of age.

The efficacy in geriatric patients has been established.

For pharmacokinetic information in geriatric patients, .

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

SNRIs and

SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction.

Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.