DRUGS & SUPPLEMENTS

Medication: Flumusa

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Flumusa uses

Flumusa consists of Alprazolam, Fluoxetine Hydrochloride.

Alprazolam:


Pharmacological action

Flumusa is an anxiolytic drug (tranquilizer), a derivative of triazolo-benzodiazepine. This medication has anxiolytic, sedative, hypnotic, anticonvulsant, central muscle relaxant effect. The mechanism of action is to enhance the inhibitory effect of endogenous GABA in the CNS by increasing the sensitivity of the GABA-receptor mediator as a result of stimulation of benzodiazepine receptors located in the allosteric center of postsynaptic GABA-receptor activating ascending reticular formation of brain stem neurons and the lateral horns of the spinal cord; reduces the excitability of the subcortical brain structures (the limbic system, thalamus, hypothalamus), inhibits the polysynaptic spinal reflexes.

Pronounced anxiolytic activity (reduction of emotional tension, easing anxiety, fear, anxiety) is combined with moderate soporific effect; it shortens the period of sleep, increases sleep duration and reduces the number of nighttime awakenings. The mechanism of hypnotic action is inhibition of cell reticular formation of the brain.

Pharmacokinetics

After oral administration Flumusa (Alprazolam) is rapidly and completely absorbed from the gastrointestinal tract. Cmax plasma levels achieved within 1-2 hours. Binding to plasma proteins is 80%. This drud metabolized in the liver. T1/2 is an average of 12-15 hours. Flumusa (Alprazolam) and its metabolites are mainly excreted by kidneys.

Why is Flumusa prescribed?

  • anxiety, neurosis accompanied by anxiety, danger, stress, deterioration of sleep, irritability, and somatic disorders
  • mixed anxiety-depressive conditions
  • neurotic reactive depression accompanied by depressed mood, loss of interest in his surroundings, anxiety, loss of sleep, decreased appetite, and somatic disorders
  • anxiety and neurotic depression that developed on the background of systemic diseases
  • panic disorder in combination and without symptoms of phobias

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    Dosage and administration

    Individual. It is recommended to use the minimum effective dose of Flumusa Aurobindo. The dose is corrected in the treatment process depending on the achieved effect and tolerability. If necessary, increase the dose should be increased gradually, first in the evening and then in the daytime reception.

    The initial dose of Flumusa (Alprazolam) is 250-500 mg 3 times / day, if necessary, it gradually increases to 4.5 mg / day.

    For elderly or debilitated patients the initial dose is 250 mg 2-3 / day, maintenance doses - 500-750 mg / day, if necessary, taking into account the tolerance dose can be increased.

    Cancellation or reduction of the dose of Flumusa (Alprazolam) should be done gradually by reducing the daily dose of no more than 500 mcg every 3 days; sometimes can needed even more slowly cancelling.

    Flumusa (Alprazolam) side effects, adverse reactions

    CNS: at the beginning of treatment (especially in elderly patients) drowsiness, fatigue, dizziness, decreased ability to concentrate, ataxia, disorientation, unsteady gait, slowing of mental and motor responses; rare - headache, euphoria, depression, tremors, memory loss, impaired coordination of movements, depressed mood, confusion, extrapyramidal dystonic reactions (involuntary movements, including for eyes), weakness, myasthenia gravis, dysarthria; in some cases - paradoxical reactions (aggressive flare, confusion, psychomotor agitation, fear, suicidal tendencies, muscle spasms, hallucinations, agitation, irritability, anxiety, insomnia).

    Digestive system: possible dry mouth or excessive salivation, heartburn, nausea, vomiting, decreased appetite, constipation or diarrhea, abnormal liver function, elevated liver transaminases and alkaline phosphatase, jaundice.

    Hematopoietic system: possible leukopenia, neutropenia, agranulocytosis (chills, pyrexia, sore throat, extreme tiredness or weakness), anemia, thrombocytopenia.

    Urinary tract: possible urinary incontinence, urinary retention, renal failure, decreased or increased libido, dysmenorrhea.

    Endocrine system: possible change in body weight, disturbances in libido, menstrual irregularities.

    Cardiovascular system: possible decrease in blood pressure, tachycardia.

    Allergic reactions: possible skin rash, itching.

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    Contraindications

    Coma, shock, myasthenia gravis, angle-closure glaucoma, acute alcohol poisoning (with the weakening of the vital functions), narcotic analgesics, hypnotics and psychotropic drugs, chronic obstructive airways disease with incipient respiratory failure, acute respiratory failure, severe depression (suicidal tendencies may occur), pregnancy (especially the I trimester), lactation, childhood and adolescence to 18 years, increased sensitivity to benzodiazepines.

    Using during pregnancy and breastfeeding

    Flumusa (Alprazolam) has a toxic effect on the fetus and increases the risk of birth defects when used in the I trimester of pregnancy. The constant use during pregnancy can cause physical dependence with the development of withdrawal syndrome in the newborn. Reception at therapeutic doses in the later stages of pregnancy can cause neonatal CNS depression. Using of Flumusa (Alprazolam) immediately before birth or during labor can cause neonatal respiratory depression, decreased muscle tone, hypotension, hypothermia and a weak act of sucking (sucking flaccid syndrome baby).

    It is possible to excretion of the benzodiazepines in breast milk that can cause drowsiness in the newborn and hinder feeding.

    In experimental studies have been shown that Flumusa (Alprazolam) and its metabolites are excreted in breast milk.

    Special instructions

    Keep in mind that anxiety or conditions related to everyday stress usually does not require treatment with anxiolytics.

    If you experience paradoxical reactions then stop taking the drug. During the period of treatment is unacceptable to use of alcoholic drinks. With caution use Flumusa for drivers of vehicles and people whose profession is associated with increased concentration.

    Flumusa (Alprazolam) drug interactions

    The simultaneous use of Flumusa (Alprazolam) with psychotropic, anticonvulsant medications and ethanol is observed enhancement inhibitory action Flumusa (Alprazolam) on the CNS.

    The simultaneous use with blockers of histamine H2-receptor reduce the clearance of Flumusa (Alprazolam) and increase the inhibitory effect of Flumusa (Alprazolam) on the CNS; macrolide antibiotics reduce the clearance of Flumusa (Alprazolam).

    The simultaneous use with hormonal oral contraceptives increased T1/2 of Flumusa (Alprazolam).

    Simultaneous administration of Flumusa (Alprazolam) with dextropropoxyphene observed a more pronounced CNS depression than in combination with other benzodiazepines, as may increase the concentration of Flumusa (Alprazolam) in blood plasma.

    Simultaneous treatment with digoxin increases the risk of intoxication by cardiac glycosides.

    Flumusa (Alprazolam) increases the concentration of imipramine in plasma.

    Simultaneous administration with itraconazole, ketoconazole increases the effects of Flumusa (Alprazolam).

    Simultaneous administration with paroxetine may increases the effects of Flumusa (Alprazolam) due to the inhibition of its metabolism.

    Fluvoxamine increases the concentration of Flumusa (Alprazolam) in plasma and risk of its side effects.

    Simultaneous administration of Flumusa (Alprazolam) with fluoxetine may increase the concentration of Flumusa (Alprazolam) in plasma by decreasing its metabolism and clearance under the influence of fluoxetine which is accompanied by psychomotor disorders.

    It can not be exclude the possibility of strengthening effect of Flumusa (Alprazolam) for simultaneous administration with erythromycin.

    Flumusa in case of emergency / overdose

    Symptoms: Varying degrees of CNS oppression (from sleepiness to coma) - drowsiness, confusion; in more severe cases (especially in patients receiving other drugs depressing the central nervous system or alcohol) - ataxia, decreased reflexes, hypotension, coma.

    Treatment: induction of vomiting, gastric lavage, symptomatic therapy, monitor vital signs. In severe hypotension prescribed an injection of norepinephrine. Specific antidote is benzodiazepine receptor antagonist flumazenil (administration only in a hospital).

  • Fluoxetine Hydrochloride:


    1 INDICATIONS AND USAGE

    Flumusa capsules, USP is a selective serotonin reuptake inhibitor indicated for:

    • Acute and maintenance treatment of Major Depressive Disorder (MDD) in adult and pediatric patients aged 8 to 18 years (1.1)
    • Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) in adult and pediatric patients aged 7 to 17 years (1.2)
    • Acute and maintenance treatment of Bulimia Nervosa in adult patients (1.3)
    • Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients (1.4)
    Flumusa (Fluoxetine Hydrochloride) capsules, USP and olanzapine in combination for:

    • Acute treatment of Depressive Episodes Associated with Bipolar I Disorder in adults (1.5)

    1.1 Major Depressive Disorder

    Flumusa (Fluoxetine Hydrochloride) capsules, USP are indicated for the acute and maintenance treatment of Major Depressive Disorder in adult patients and in pediatric patients aged 8 to18 years [see Clinical Studies (14.1)].

    The usefulness of the drug in adult and pediatric patients receiving Flumusa (Fluoxetine Hydrochloride) for extended periods, should periodically be re-evaluated [see Dosage and Administration (2.1)].

    1.2 Obsessive Compulsive Disorder

    Flumusa capsules, USP are indicated for the acute and maintenance treatment of obsessions and compulsions in adult patients and in pediatric patients aged 7 to 17 years with Obsessive Compulsive Disorder (OCD) [see Clinical Studies (14.2)].

    The effectiveness of Flumusa (Fluoxetine Hydrochloride) capsules, USP in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use Flumusa (Fluoxetine Hydrochloride) capsules, USP for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.2)].

    1.3 Bulimia Nervosa

    Flumusa (Fluoxetine Hydrochloride) capsules, USP are indicated for the acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa [see Clinical Studies (14.3)].

    The physician who elects to use Flumusa (Fluoxetine Hydrochloride) capsules, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)].

    1.4 Panic Disorder

    Flumusa capsules, USP are indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients [see Clinical Studies (14.4)].

    The effectiveness of Flumusa (Fluoxetine Hydrochloride) capsules, USP in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use Flumusa (Fluoxetine Hydrochloride) capsules, USP for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.4)].

    1.5 Flumusa (Fluoxetine Hydrochloride) Capsules, USP and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder

    When using Flumusa (Fluoxetine Hydrochloride) capsules, USP and olanzapine in combination, also refer to the Clinical Studies section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules .

    Flumusa (Fluoxetine Hydrochloride) capsules, USP and olanzapine in combination is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder in adult patients.

    Flumusa (Fluoxetine Hydrochloride) capsules, USP monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

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    2 DOSAGE AND ADMINISTRATION

    Indication Adult Pediatric
    MDD 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose)
    OCD (2.2) 20 mg/day in am (initial dose) 10 mg/day (initial dose)
    Bulimia Nervosa (2.3) 60 mg/day in am -
    Panic Disorder (2.4) 10 mg/day (initial dose) -
    Depressive Episodes Associated with Bipolar I Disorder (2.5) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of Flumusa (Fluoxetine Hydrochloride) once daily (initial dose) -
    • Consider tapering the dose of Flumusa (Fluoxetine Hydrochloride) for pregnant women during the third trimester (2.7)
    • 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 (2.7)
    Flumusa (Fluoxetine Hydrochloride) capsules and olanzapine in combination:

    • Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability (2.5)
    • Flumusa (Fluoxetine Hydrochloride) monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder (2.5)
    • Safety of the coadministration of doses above 18 mg olanzapine with 75 mg Flumusa (Fluoxetine Hydrochloride) has not been evaluated (2.5)

    2.1 Major Depressive Disorder

    Initial Treatment

    Adult — In controlled trials used to support the efficacy of Flumusa (Fluoxetine Hydrochloride), patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing Flumusa (Fluoxetine Hydrochloride) 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. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose.

    A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day.

    Pediatric (children and adolescents) — In the short-term (8 to 9 week) controlled clinical trials of Flumusa (Fluoxetine Hydrochloride) supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered Flumusa (Fluoxetine Hydrochloride) doses of 10 to 20 mg/day [see Clinical Studies (14.1)]. Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased 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. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed.

    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.

    Maintenance/Continuation/Extended Treatment — It is generally agreed that acute episodes of Major Depressive Disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

    Daily Dosing — Systematic evaluation of Flumusa (Fluoxetine Hydrochloride) capsules in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day [see Clinical Studies (14.1)].

    Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when Flumusa (Fluoxetine Hydrochloride) is coadministered or has been recently discontinued [see Drug Interactions (7.9)].

    Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) — At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Flumusa (Fluoxetine Hydrochloride) capsules. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping Flumusa (Fluoxetine Hydrochloride) capsules before starting an MAOI [see Contraindications (4) and Drug Interactions (7.1)].

    2.2 Obsessive Compulsive Disorder

    Initial Treatment

    Adult — In the controlled clinical trials of Flumusa supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of Flumusa (Fluoxetine Hydrochloride) or placebo [see Clinical Studies (14.2)]. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer.

    Doses above 20 mg/day may be administered on a once daily (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 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 Flumusa (Fluoxetine Hydrochloride) dose should not exceed 80 mg/day.

    Pediatric (children and adolescents) — In the controlled clinical trial of Flumusa (Fluoxetine Hydrochloride) supporting its effectiveness in the treatment of OCD, patients were administered Flumusa (Fluoxetine Hydrochloride) doses in the range of 10 to 60 mg/day [see Clinical Studies (14.2)].

    In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended.

    In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 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.

    Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue Flumusa (Fluoxetine Hydrochloride) capsules, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of Flumusa (Fluoxetine Hydrochloride) capsules after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment.

    2.3 Bulimia Nervosa

    Initial Treatment — In the controlled clinical trials of Flumusa (Fluoxetine Hydrochloride) supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily Flumusa (Fluoxetine Hydrochloride) doses of 20 or 60 mg, or placebo [see Clinical Studies (14.3)]. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Flumusa (Fluoxetine Hydrochloride) doses above 60 mg/day have not been systematically studied in patients with bulimia.

    Maintenance/Continuation Treatment — Systematic evaluation of continuing Flumusa (Fluoxetine Hydrochloride) capsules 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking Flumusa (Fluoxetine Hydrochloride) capsules 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment [see Clinical Studies (14.3)]. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

    2.4 Panic Disorder

    Initial Treatment — In the controlled clinical trials of Flumusa supporting its effectiveness in the treatment of Panic Disorder, patients were administered Flumusa (Fluoxetine Hydrochloride) doses in the range of 10 to 60 mg/day [see Clinical Studies (14.4)]. Treatment should be initiated with a dose of 10 mg/day. After one week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day.

    A dose increase may be considered after several weeks if no clinical improvement is observed. Flumusa (Fluoxetine Hydrochloride) doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder.

    Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue Flumusa (Fluoxetine Hydrochloride) capsules, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment.

    2.5 Flumusa (Fluoxetine Hydrochloride) Capsules and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder

    When using Flumusa (Fluoxetine Hydrochloride) capsules and olanzapine in combination, also refer to the Clinical Studies section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules.

    Flumusa (Fluoxetine Hydrochloride) should be administered 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 Flumusa (Fluoxetine Hydrochloride). Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of Flumusa (Fluoxetine Hydrochloride) 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and Flumusa (Fluoxetine Hydrochloride) in combination with a dose range of olanzapine 6 to 12 mg and Flumusa (Fluoxetine Hydrochloride) 25 to 50 mg.

    Safety and efficacy of Flumusa (Fluoxetine Hydrochloride) in combination with olanzapine was determined in clinical trials supporting approval of olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules (fixed-dose combination of olanzapine and Flumusa (Fluoxetine Hydrochloride)). Olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules 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 Flumusa (Fluoxetine Hydrochloride) capsules and olanzapine versus olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

    1Olanzapine/fluoxetine HCl is a fixed-dose combination of Flumusa (Fluoxetine Hydrochloride) capsules and olanzapine.

    For Olanzapine and Flumusa (Fluoxetine Hydrochloride) Hydrochloride Capsules (mg/day) Use in Combination
    Olanzapine (mg/day) Flumusa (Fluoxetine Hydrochloride) capsules (mg/day)
    3 mg olanzapine/25 mg Flumusa (Fluoxetine Hydrochloride) 2.5 20
    6 mg olanzapine/25 mg Flumusa (Fluoxetine Hydrochloride) 5 20
    12 mg olanzapine/25 mg Flumusa (Fluoxetine Hydrochloride) 10 + 2.5 20
    6 mg olanzapine/50 mg Flumusa (Fluoxetine Hydrochloride) 5 40 + 10
    12 mg olanzapine/50 mg Flumusa (Fluoxetine Hydrochloride) 10 + 2.5 40 + 10
    While there is no body of evidence to answer the question of how long a patient treated with Flumusa (Fluoxetine Hydrochloride) capsules and olanzapine in combination should remain on it, it is generally accepted that Bipolar I Disorder, including the depressive episodes associated with Bipolar I Disorder, is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy.

    Safety of coadministration of doses above 18 mg olanzapine with 75 mg Flumusa (Fluoxetine Hydrochloride) has not been evaluated in clinical studies.

    Flumusa (Fluoxetine Hydrochloride) 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 during the Third Trimester — When treating pregnant women with Flumusa capsules during the third trimester, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. The physician may consider tapering Flumusa (Fluoxetine Hydrochloride) capsules in the third trimester [see Use in Specific Populations (8.1)].

    Geriatric — A lower or less frequent dosage should be considered for the elderly [see Use in Specific Populations (8.5)]

    Hepatic Impairment — As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment [see Clinical Pharmacology (12.4) and Use in Specific Populations (8.6)].

    Concomitant Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see Clinical Pharmacology (12.4) and Warnings and Precautions (5.10)].

    Flumusa (Fluoxetine Hydrochloride) Capsules and Olanzapine in Combination — The starting dose of oral olanzapine 2.5 to 5 mg with Flumusa (Fluoxetine Hydrochloride) 20 mg should be used 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 Flumusa (Fluoxetine Hydrochloride) in combination (female gender, geriatric age, non-smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modifications may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Flumusa (Fluoxetine Hydrochloride) capsules and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 18 years of age [see Warnings and Precautions (5.14) and Drug Interactions (7.9)].

    2.8 Discontinuation of Treatment

    Symptoms associated with discontinuation of Flumusa (Fluoxetine Hydrochloride), SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.13)].

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    3 DOSAGE FORMS AND STRENGTHS

    • 40 mg capsule are green opaque cap with orange opaque body, hard gelatin #2 capsules filled with white to off-white powder, imprinted with “RX632” on the cap and body in black ink.
    • Capsules: 40 mg (3)

    4 CONTRAINDICATIONS

    When using Flumusa (Fluoxetine Hydrochloride) and olanzapine in combination, also refer to the Contraindications section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules.

    The use of Flumusa (Fluoxetine Hydrochloride) is contraindicated with the following:

    • Monoamine Oxidase Inhibitors [see Drug Interactions (7.1)]
    • Pimozide [see Drug Interactions (7.9)]
    • Thioridazine [ see Drug Interactions (7.9) ]
    • Do not use with an MAOI or within 14 days of discontinuing an MAOI due to risk of drug interaction. At least 5 weeks should be allowed after stopping Flumusa (Fluoxetine Hydrochloride) before treatment with an MAOI (4, 7.1)
    • Do not use with pimozide due to risk of drug interaction or QTc prolongation (4, 7.9)
    • Do not use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing Flumusa (Fluoxetine Hydrochloride) (4, 7.9)
    • When using Flumusa (Fluoxetine Hydrochloride) and olanzapine in combination, also refer to the Contraindications section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules (4)

    5 WARNINGS AND PRECAUTIONS

    When using Flumusa and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules.

    • Clinical Worsening and Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior (5.1)
    • Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: Have been reported with Flumusa (Fluoxetine Hydrochloride). Discontinue Flumusa (Fluoxetine Hydrochloride) and initiate supportive treatment (5.2)
    • Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena (5.3)
    • Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania (5.4)
    • Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold (5.5)
    • Altered Appetite and Weight: Significant weight loss has occurred (5.6)
    • Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.7)
    • Hyponatremia : Has been reported with Flumusa (Fluoxetine Hydrochloride) in association with syndrome of inappropriate antidiuretic hormone (SIADH) (5.8)
    • Anxiety and Insomnia: May occur (5.9)
    • Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery (5.11)
    • Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks (5.12)
    • Flumusa (Fluoxetine Hydrochloride) and Olanzapine in Combination: When using Flumusa (Fluoxetine Hydrochloride) and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules (5.14)

    5.1 Clinical Worsening and Suicide Risk

    Patients with Major Depressive Disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with Major Depressive Disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

    The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.

    Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
    Increases Compared to Placebo
    < 18 14 additional cases
    18 to 24 5 additional cases
    Decreases Compared to Placebo
    25 to 64 1 fewer case
    ≥ 65 6 fewer cases
    No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

    It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

    All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

    The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for Major Depressive Disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

    Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

    If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.13)].

    Families and caregivers of patients being treated with antidepressants for Major Depressive Disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Flumusa (Fluoxetine Hydrochloride) should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

    It should be noted that Flumusa (Fluoxetine Hydrochloride) is approved in the pediatric population only for Major Depressive Disorder and Obsessive Compulsive Disorder. Safety and effectiveness of Flumusa (Fluoxetine Hydrochloride) and olanzapine in combination in patients less than 18 years of age have not been established.

    5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome -like Reactions

    The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Flumusa (Fluoxetine Hydrochloride) treatment, but particularly with concomitant use of serotonergic drugs (including triptans), with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

    The concomitant use of Flumusa (Fluoxetine Hydrochloride) with MAOIs intended to treat depression is contraindicated [see Contraindications (4) and Drug Interactions (7.1)].

    If concomitant treatment of Flumusa (Fluoxetine Hydrochloride) with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions (7.4)].

    The concomitant use of Flumusa (Fluoxetine Hydrochloride) with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions (7.3)].

    Treatment with Flumusa (Fluoxetine Hydrochloride) and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated.

    5.3 Allergic Reactions and Rash

    In US Flumusa clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of Flumusa (Fluoxetine Hydrochloride) and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely.

    In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness.

    Since the introduction of Flumusa (Fluoxetine Hydrochloride), systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions.

    Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported.

    Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom.

    Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, Flumusa (Fluoxetine Hydrochloride) should be discontinued.

    5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania

    A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for Bipolar Disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for Bipolar Disorder; such screening should include a detailed psychiatric history, including a family history of suicide, Bipolar Disorder, and depression. It should be noted that Flumusa (Fluoxetine Hydrochloride) and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder [see Warnings and Precautions section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules ]. Flumusa (Fluoxetine Hydrochloride) monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

    In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with Flumusa (Fluoxetine Hydrochloride) and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [see Use in Specific Populations (8.4)].

    In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with Flumusa (Fluoxetine Hydrochloride) and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In US Flumusa (Fluoxetine Hydrochloride) clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations (8.4)].

    5.5 Seizures

    In US placebo-controlled clinical trials for Major Depressive Disorder, convulsions were reported in 0.1% of patients treated with Flumusa (Fluoxetine Hydrochloride) and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In US Flumusa (Fluoxetine Hydrochloride) clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder. Flumusa (Fluoxetine Hydrochloride) should be introduced with care in patients with a history of seizures.

    5.6 Altered Appetite and Weight

    Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with Flumusa (Fluoxetine Hydrochloride).

    In US placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with Flumusa (Fluoxetine Hydrochloride) and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with Flumusa (Fluoxetine Hydrochloride) and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with Flumusa (Fluoxetine Hydrochloride) because of anorexia or weight loss [see Use in Specific Populations (8.4)].

    In US placebo-controlled clinical trials for OCD, 17% of patients treated with Flumusa (Fluoxetine Hydrochloride) and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Flumusa (Fluoxetine Hydrochloride) because of anorexia [see Use in Specific Populations (8.4)].

    In US placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with Flumusa (Fluoxetine Hydrochloride) 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with Flumusa (Fluoxetine Hydrochloride) 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy.

    5.7 Abnormal Bleeding

    SNRIs and SSRIs, including Flumusa, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

    Patients should be cautioned about the risk of bleeding associated with the concomitant use of Flumusa (Fluoxetine Hydrochloride) and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.6)].

    5.8 Hyponatremia

    Hyponatremia has been reported during treatment with SNRIs and SSRIs, including Flumusa (Fluoxetine Hydrochloride). In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Flumusa (Fluoxetine Hydrochloride) was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of Flumusa (Fluoxetine Hydrochloride) should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

    Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

    5.9 Anxiety and Insomnia

    In US placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with Flumusa and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.

    In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with Flumusa (Fluoxetine Hydrochloride) and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with Flumusa (Fluoxetine Hydrochloride) and in 7% of patients treated with placebo.

    In US placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with Flumusa (Fluoxetine Hydrochloride) 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with Flumusa (Fluoxetine Hydrochloride) 60 mg and in 9% and 5% of patients treated with placebo.

    Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for Flumusa (Fluoxetine Hydrochloride) in clinical trials collecting only a primary reaction associated with discontinuation) in US placebo-controlled Flumusa (Fluoxetine Hydrochloride) clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) .

    5.10 Use in Patients with Concomitant Illness

    Clinical experience with Flumusa (Fluoxetine Hydrochloride) in patients with concomitant systemic illness is limited. Caution is advisable in using Flumusa (Fluoxetine Hydrochloride) in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

    Cardiovascular — Flumusa (Fluoxetine Hydrochloride) has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received Flumusa (Fluoxetine Hydrochloride) in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min.

    Glycemic Control — In patients with diabetes, Flumusa (Fluoxetine Hydrochloride) may alter glycemic control. Hypoglycemia has occurred during therapy with Flumusa (Fluoxetine Hydrochloride), and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with Flumusa (Fluoxetine Hydrochloride) is instituted or discontinued.

    Acute Narrow-Angle Glaucoma — Mydriasis has been reported in association with Flumusa (Fluoxetine Hydrochloride); therefore, caution should be used when prescribing Flumusa (Fluoxetine Hydrochloride) in patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma.

    5.11 Potential for Cognitive and Motor Impairment

    As with any CNS-active drug, Flumusa has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.

    5.12 Long Elimination Half-Life

    Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with Flumusa (Fluoxetine Hydrochloride) and norfluoxetine following the discontinuation of Flumusa (Fluoxetine Hydrochloride) [see Clinical Pharmacology (12.3)].

    5.13 Discontinuation of Treatment

    During marketing of Flumusa, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Flumusa (Fluoxetine Hydrochloride). A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma Flumusa (Fluoxetine Hydrochloride) and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug.

    5.14 Fluoxetine and Olanzapine in Combination

    When using Flumusa (Fluoxetine Hydrochloride) and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules.

    6 ADVERSE REACTIONS

    When using Flumusa and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules.

    Most common adverse reactions (≥ 5% and at least twice that for placebo) associated with:

    Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1)

    Flumusa (Fluoxetine Hydrochloride) and olanzapine in combination – Also refer to the Adverse Reactions section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules (6)

    To report SUSPECTED ADVERSE REACTIONS, contact Ranbaxy Pharmaceuticals Inc. at 1-888-Ranbaxy (726-2299) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

    6.1 Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

    Multiple doses of Flumusa (Fluoxetine Hydrochloride) had been administered to 10,782 patients with various diagnoses in US clinical trials. In addition, there have been 425 patients administered Flumusa (Fluoxetine Hydrochloride) in panic clinical trials. Adverse reactions were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited (i.e., reduced) number of standardized reaction categories.

    In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that reactions reported during therapy were not necessarily caused by it.

    The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

    Incidence in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 3 enumerates the most common treatment-emergent adverse reactions associated with the use of Flumusa (Fluoxetine Hydrochloride) (incidence of at least 5% for Flumusa (Fluoxetine Hydrochloride) and at least twice that for placebo within at least 1 of the indications) for the treatment of Major Depressive Disorder, OCD, and bulimia in US controlled clinical trials and Panic Disorder in US plus non-US controlled trials. Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with Flumusa (Fluoxetine Hydrochloride) and with incidence greater than placebo who participated in US Major Depressive Disorder, OCD, and bulimia controlled clinical trials and US plus non-US Panic Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are provided separately by indication in Table 3.

    Percentage of Patients Reporting Event
    Major Depressive Disorder OCD Bulimia Panic Disorder
    Body System/ A dverse Reaction Flumusa (Fluoxetine Hydrochloride) (N = 1728) Placebo (N = 975) Flumusa (Fluoxetine Hydrochloride) (N = 266) Placebo (N = 89) Flumusa (Fluoxetine Hydrochloride) (N = 450) Placebo (N = 267) Flumusa (Fluoxetine Hydrochloride) (N = 425) Placebo (N = 342)
    Body as a Whole
    Asthenia 9 5 15 11 21 9 7 7
    Flu syndrome 3 4 10 7 8 3 5 5
    Cardiovascular System
    Vasodilatation 3 2 5 -- 2 1 1 --
    Digestive System
    Nausea 21 9 26 13 29 11 12 7
    Diarrhea 12 8 18 13 8 6 9 4
    Anorexia 11 2 17 10 8 4 4 1
    Dry mouth 10 7 12 3 9 6 4 4
    Dyspepsia 7 5 10 4 10 6 6 2
    Nervous System
    Insomnia 16 9 28 22 33 13 10 7
    Anxiety 12 7 14 7 15 9 6 2
    Nervousness 14 9 14 15 11 5 8 6
    Somnolence 13 6 17 7 13 5 5 2
    Tremor 10 3 9 1 13 1 3 1
    Libido decreased 3 -- 11 2 5 1 1 2
    Abnormal dreams 1 1 5 2 5 3 1 1
    Respiratory System
    Pharyngitis 3 3 11 9 10 5 3 3
    Sinusitis 1 4 5 2 6 4 2 3
    Yawn -- -- 7 -- 11 -- 1 --
    Skin and Appendages
    Sweating 8 3 7 -- 8 3 2 2
    Rash 4 3 6 3 4 4 2 2
    Urogenital System
    Impotence3 2 -- -- -- 7 -- 1 --
    Abnormal ejaculation3 -- -- 7 -- 7 -- 2 1
    1 Incidence less than 1%.

    2 Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials.

    3 Denominator used was for males only (N = 690 Flumusa (Fluoxetine Hydrochloride) Major Depressive Disorder; N = 410 placebo Major Depressive Disorder; N = 116 Flumusa (Fluoxetine Hydrochloride) OCD; N = 43 placebo OCD; N = 14 Flumusa (Fluoxetine Hydrochloride) bulimia; N = 1 placebo bulimia; N = 162 Flumusa (Fluoxetine Hydrochloride) panic; N = 121 placebo panic).

    Percentage of Patients Reporting Event
    Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined
    Body System/ Adverse Reaction Flumusa (Fluoxetine Hydrochloride) ( N = 2869) Placebo (N = 1673)
    Body as a Whole
    Headache 21 19
    Asthenia 11 6
    Flu syndrome 5 4
    Fever 2 1
    Cardiovascular System
    Vasodilatation 2 1
    Digestive System
    Nausea 22 9
    Diarrhea 11 7
    Anorexia 10 3
    Dry mouth 9 6
    Dyspepsia 8 4
    Constipation 5 4
    Flatulence 3 2
    Vomiting 3 2
    Metabolic and Nutritional Disorders
    Weight loss 2 1
    Nervous System
    Insomnia 19 10
    Nervousness 13 8
    Anxiety 12 6
    Somnolence 12 5
    Dizziness 9 6
    Tremor 9 2
    Libido decreased 4 1
    Thinking abnormal 2 1
    Respiratory System
    Yawn 3 --
    Skin and Appendages
    Sweating 7 3
    Rash 4 3
    Pruritus 3 2
    Special Senses
    Abnormal vision 2 1
    1 Incidence less than 1%.

    2 Includes US data for Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials.

    Associated with discontinuation in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 5 lists the adverse reactions associated with discontinuation of Flumusa (Fluoxetine Hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for Flumusa (Fluoxetine Hydrochloride) in clinical trials collecting only a primary reaction associated with discontinuation) in Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials.

    Major Depressive D isorder, OCD, Bu limia, and PanicD is order Combined(N = 1533) Major D epressive D isorder(N = 392) OCD(N = 266) Bulimia(N = 450) Panic Disorder(N = 425)
    Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%)
    -- -- -- Insomnia (2%) --
    -- Nervousness (1%) -- -- Nervousness (1%)
    -- -- Rash (1%) -- --
    1 Includes US Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials.

    Other adverse reactions in pediatric patients (children and adolescents) — Treatment-emergent adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for Flumusa (Fluoxetine Hydrochloride) and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia.

    The most common adverse reaction (incidence at least 1% for Flumusa (Fluoxetine Hydrochloride) and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N = 418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with discontinuation was collected.

    Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US Major Depressive Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking Flumusa (Fluoxetine Hydrochloride) (4% Flumusa (Fluoxetine Hydrochloride), < 1% placebo). There have been spontaneous reports in women taking Flumusa (Fluoxetine Hydrochloride) of orgasmic dysfunction, including anorgasmia.

    There are no adequate and well-controlled studies examining sexual dysfunction with Flumusa (Fluoxetine Hydrochloride) treatment.

    Symptoms of sexual dysfunction occasionally persist after discontinuation of Flumusa (Fluoxetine Hydrochloride) treatment.

    Priapism has been reported with all SSRIs.

    While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

    6.2 Other Reactions

    Following is a list of treatment-emergent adverse reactions reported by patients treated with Flumusa in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

    Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

    Body as a Whole Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction.

    Cardiovascular SystemFrequent: palpitation; Infrequent: arrhythmia, hypotension1.

    Digestive System Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage.

    Hemic and Lymphatic System Infrequent: ecchymosis; Rare: petechia, purpura.

    Nervous System Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder1, bruxism1, buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions.

    Respiratory System Rare: larynx edema.

    Skin and AppendagesInfrequent: alopecia; Rare: purpuric rash.

    Special Senses Frequent: taste perversion; Infrequent: mydriasis.

    Urogenital SystemFrequent: micturition disorder; Infrequent: dysuria, gynecological bleeding2 .

    1 MedDRA dictionary term from integrated database of placebo controlled trials of 15870 patients, of which 9673 patients received Flumusa (Fluoxetine Hydrochloride).

    2 Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender.

    6.3 Postmarketing Experience

    The following adverse reactions have been identified during post approval use of Flumusa (Fluoxetine Hydrochloride). Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

    Voluntary reports of adverse reactions temporally associated with Flumusa (Fluoxetine Hydrochloride) that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation 1, cataract, cerebrovascular accident1, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of Flumusa (Fluoxetine Hydrochloride) therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia1, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of pre-existing movement disorders, optic neuritis, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including torsades de pointes–type arrhythmias), vaginal bleeding, and violent behaviors1.

    1 These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

    7 DRUG INTERACTIONS

    As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

    • Monoamine Oxidase Inhibitors (MAOI): Flumusa (Fluoxetine Hydrochloride) is contraindicated for use with MAOI’s, or within 14 days of discontinuing an MAOI due to risk of drug interaction. At least 5 weeks should be allowed after stopping Flumusa (Fluoxetine Hydrochloride) before starting treatment with an MAOI (4, 7.1)
    • Pimozide: Flumusa (Fluoxetine Hydrochloride) is contraindicated for use with pimozide due to risk of drug interaction or QTc prolongation (4, 7.9)
    • Thioridazine: Flumusa (Fluoxetine Hydrochloride) is contraindicated for use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing Flumusa (Fluoxetine Hydrochloride) (4, 7.9)
    • Drugs Metabolized by CYP2D6: Flumusa (Fluoxetine Hydrochloride) is a potent inhibitor of CYP2D6 enzyme pathway (7.9)
    • Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with Flumusa (Fluoxetine Hydrochloride) or when Flumusa (Fluoxetine Hydrochloride) has been recently discontinued (7.9)
    • CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs (7.2)
    • Benzodiazepines: Diazepam – increased t½, alprazolam - further psychomotor performance decrement due to increased levels (7.9)
    • Antipsychotics: Potential for elevation of haloperidol and clozapine levels (7.9)
    • Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.9)
    • Serotonergic Drugs: Potential for Serotonin Syndrome (5.2, 7.3)
    • Triptans: There have been rare postmarketing reports of Serotonin Syndrome with use of an SSRI and a triptan (5.2, 7.4)
    • Tryptophan: Concomitant use with tryptophan is not recommended (5.2, 7.5)
    • Drugs that Interfere with Hemostasis (e.g. NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding (7.6)
    • Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations (7.8, 7.9)
    • Olanzapine: When used in combination with Flumusa (Fluoxetine Hydrochloride), also refer to the Drug Interactions section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules (7.9)

    7.1 Monoamine Oxidase Inhibitors (MAOI)

    There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving Flumusa (Fluoxetine Hydrochloride) in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued Flumusa (Fluoxetine Hydrochloride) and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Flumusa (Fluoxetine Hydrochloride) should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Contraindications (4)]. Since Flumusa (Fluoxetine Hydrochloride) and its major metabolite have very long elimination half-lives, at least 5 weeks (perhaps longer, especially if Flumusa (Fluoxetine Hydrochloride) has been prescribed chronically and/or at higher doses) should be allowed after stopping Flumusa (Fluoxetine Hydrochloride) before starting an MAOI [see Clinical Pharmacology (12.3)].

    7.2 CNS Acting Drugs

    Caution is advised if the concomitant administration of Flumusa and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology (12.3)].

    7.3 Serotonergic Drugs

    Based on the mechanism of action of SNRIs and SSRIs, including Flumusa (Fluoxetine Hydrochloride), and the potential for serotonin syndrome, caution is advised when Flumusa (Fluoxetine Hydrochloride) is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort [see Warnings and Precautions (5.2)]. The concomitant use of Flumusa (Fluoxetine Hydrochloride) with SNRIs, SSRIs, or tryptophan is not recommended [see Drug Interactions (7.4), (7.5)].

    7.4 Triptans

    There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Flumusa with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions (5.2) and Drug Interactions (7.3)].

    7.5 Tryptophan

    Five patients receiving Flumusa (Fluoxetine Hydrochloride) in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. The concomitant use with tryptophan is not recommended [see Warnings and Precautions (5.2) and Drug Interactions (7.3)].

    7.6 Drugs that Interfere with Hemostasis

    Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Flumusa (Fluoxetine Hydrochloride) is initiated or discontinued [see Warnings and Precautions (5.7)].

    7.7 Electroconvulsive Therapy

    There are no clinical studies establishing the benefit of the combined use of ECT and Flumusa (Fluoxetine Hydrochloride). There have been rare reports of prolonged seizures in patients on Flumusa (Fluoxetine Hydrochloride) receiving ECT treatment.

    7.8 Potential for Other Drugs to affect Flumusa

    Drugs Tightly Bound to Plasma Proteins – Because Flumusa (Fluoxetine Hydrochloride) is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound Flumusa (Fluoxetine Hydrochloride) by other tightly-bound drugs [see Clinical Pharmacology (12.3)].

    7.9 Potential for Flumusa to affect Other Drugs

    Pimozide – Concomitant use in patients taking pimozide is contraindicated. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and Flumusa (Fluoxetine Hydrochloride) has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and Flumusa (Fluoxetine Hydrochloride) [see Contraindications (4)].

    Thioridazine – Thioridazine should not be administered with Flumusa (Fluoxetine Hydrochloride) or within a minimum of 5 weeks after Flumusa (Fluoxetine Hydrochloride) has been discontinued [see Contraindications (4)].

    In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including Flumusa (Fluoxetine Hydrochloride), will produce elevated plasma levels of thioridazine.

    Thioridazine administration produces a dose-related prolongation of the QT c interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism.

    Drugs Metabolized by CYP2D6 – Flumusa (Fluoxetine Hydrochloride) inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of Flumusa (Fluoxetine Hydrochloride) with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving Flumusa (Fluoxetine Hydrochloride) concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If Flumusa (Fluoxetine Hydrochloride) is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with Flumusa (Fluoxetine Hydrochloride) or within a minimum of 5 weeks after Flumusa (Fluoxetine Hydrochloride) has been discontinued [see Contraindications (4)].

    Tricyclic Antidepressants (TCAs) — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when Flumusa (Fluoxetine Hydrochloride) has been administered in combination. This influence may persist for 3 weeks or longer after Flumusa (Fluoxetine Hydrochloride) is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when Flumusa (Fluoxetine Hydrochloride) is coadministered or has been recently discontinued [see Clinical Pharmacology (12.3)].

    Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3)]. Coadministration of alprazolam and Flumusa (Fluoxetine Hydrochloride) has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

    Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant Flumusa (Fluoxetine Hydrochloride) [see Contraindications (4)].

    Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant Flumusa (Fluoxetine Hydrochloride) treatment.

    Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with Flumusa (Fluoxetine Hydrochloride). Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.

    Drugs Tightly Bound to Plasma Proteins — Because Flumusa (Fluoxetine Hydrochloride) is tightly bound to plasma proteins, the administration of Flumusa (Fluoxetine Hydrochloride) to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect [see Clinical Pharmacology (12.3)].

    Drugs Metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of Flumusa (Fluoxetine Hydrochloride) with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant Flumusa (Fluoxetine Hydrochloride).

    Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than Flumusa (Fluoxetine Hydrochloride) or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

    Olanzapine— Flumusa (Fluoxetine Hydrochloride) (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended.

    When using Flumusa (Fluoxetine Hydrochloride) and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules.

    8 USE IN SPECIFIC POPULATIONS

    When using Flumusa and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules.

    • Pregnancy: Flumusa (Fluoxetine Hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus (8.1)
    • Nursing Mothers: Breast feeding is not recommended (8.3)
    • Pediatric Use: Safety and effectiveness of Flumusa (Fluoxetine Hydrochloride) and olanzapine in combination have not been established in patients less than 18 years of age (8.4)
    • Hepatic Impairment: Lower or less frequent dosing may be appropriate in patients with cirrhosis (8.6)

    8.1 Pregnancy

    Pregnancy Category C — Flumusa (Fluoxetine Hydrochloride) 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 Flumusa (Fluoxetine Hydrochloride) in pregnant women. Results of a number of published epidemiological studies assessing the risk of Flumusa (Fluoxetine Hydrochloride) 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 Flumusa (Fluoxetine Hydrochloride) during the first trimester of pregnancy compared to infants of women (N = 1,359) who were not exposed to Flumusa (Fluoxetine Hydrochloride). There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established.

    Treatment of Pregnant Women during the Third Trimester — Neonates exposed to Flumusa (Fluoxetine Hydrochloride), SNRIs, or SSRIs 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 SNRIs and SSRIs 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 late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.

    Clinical Considerations When treating pregnant women with Flumusa (Fluoxetine Hydrochloride), the physician should carefully consider both the potential risks and potential benefits of treatment, taking into account the risk of untreated depression during pregnancy. Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

    The physician may consider tapering Flumusa (Fluoxetine Hydrochloride) in the third trimester [see Dosage and Administration (2.7)].

    Animal Data — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of Flumusa (Fluoxetine Hydrochloride) 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/m2 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/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 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/m2 basis).

    8.2 Labor and Delivery

    The effect of Flumusa on labor and delivery in humans is unknown. However, because Flumusa (Fluoxetine Hydrochloride) crosses the placenta and because of the possibility that Flumusa (Fluoxetine Hydrochloride) may have adverse effects on the newborn, Flumusa (Fluoxetine Hydrochloride) should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

    8.3 Nursing Mothers

    Because Flumusa (Fluoxetine Hydrochloride) is excreted in human milk, nursing while on Flumusa (Fluoxetine Hydrochloride) is not recommended. In one breast-milk sample, the concentration of Flumusa (Fluoxetine Hydrochloride) plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on Flumusa (Fluoxetine Hydrochloride) developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of Flumusa (Fluoxetine Hydrochloride) and 208 ng/mL of norfluoxetine on the second day of feeding.

    8.4 Pediatric Use

    The efficacy of Flumusa for the treatment of Major Depressive Disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤ 18 [see Clinical Studies (14.1)].

    The efficacy of Flumusa (Fluoxetine Hydrochloride) for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to < 18 [see Clinical Studies (14.2 ) ].

    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.

    Flumusa (Fluoxetine Hydrochloride) pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤ 18) with Major Depressive Disorder or OCD [see Clinical Pharmacology (12.3)].

    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 Flumusa (Fluoxetine Hydrochloride). 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 Flumusa (Fluoxetine Hydrochloride) [see Adverse Reactions (6.1)].

    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 Flumusa (Fluoxetine Hydrochloride) in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with Flumusa (Fluoxetine Hydrochloride) gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. In addition, Flumusa (Fluoxetine Hydrochloride) treatment was associated with a decrease in alkaline phosphatase levels. The safety of Flumusa (Fluoxetine Hydrochloride) 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 Flumusa (Fluoxetine Hydrochloride) on the growth, development and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving Flumusa (Fluoxetine Hydrochloride). [see Warnings and Precautions (5.6)].

    Flumusa (Fluoxetine Hydrochloride) is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1)]. Anyone considering the use of Flumusa (Fluoxetine Hydrochloride) in a child or adolescent must balance the potential risks with the clinical need.

    Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to Flumusa (Fluoxetine Hydrochloride). Some of these effects occurred at clinically relevant exposures.

    In a study in which Flumusa (Fluoxetine Hydrochloride) (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with Flumusa (Fluoxetine Hydrochloride) during the juvenile period have not been reported after administration of Flumusa (Fluoxetine Hydrochloride) to adult animals. Plasma exposures (AUC) to Flumusa (Fluoxetine Hydrochloride) in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, pediatric exposure at the MRD.

    A specific effect of Flumusa (Fluoxetine Hydrochloride) on bone development has been reported in mice treated with Flumusa (Fluoxetine Hydrochloride) during the juvenile period. When mice were treated with Flumusa (Fluoxetine Hydrochloride) (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m 2) basis.

    In another mouse study, administration of Flumusa (Fluoxetine Hydrochloride) (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increase shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m 2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain.

    Safety and effectiveness of Flumusa (Fluoxetine Hydrochloride) and olanzapine in combination in patients less than 18 years of age have not been established.

    8.5 Geriatric Use

    US Flumusa (Fluoxetine Hydrochloride) clinical trials included 687 patients ≥ 65 years of age and 93 patients ≥ 75 years of age. The efficacy in geriatric patients has been established [see Clinical Studies (14.1)]. For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.4)]. 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 Flumusa (Fluoxetine Hydrochloride), have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.8)].

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

    8.6 Hepatic Impairment

    In subjects with cirrhosis of the liver, the clearances of Flumusa (Fluoxetine Hydrochloride) and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of Flumusa (Fluoxetine Hydrochloride) should be used in patients with cirrhosis. Caution is advised when using Flumusa (Fluoxetine Hydrochloride) in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.7) and Clinical Pharmacology (12.4)].

    9 DRUG ABUSE AND DEPENDENCE

    9.3 Dependence

    Flumusa (Fluoxetine Hydrochloride) has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with Flumusa (Fluoxetine Hydrochloride) did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Flumusa (Fluoxetine Hydrochloride) (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

    10 OVERDOSAGE

    10.1 Human Experience

    Worldwide exposure to Flumusa hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving Flumusa (Fluoxetine Hydrochloride) hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths.

    Among 633 adult patients who overdosed on Flumusa (Fluoxetine Hydrochloride) hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of Flumusa (Fluoxetine Hydrochloride) hydrochloride in adult patients was 8 grams in a patient who took Flumusa (Fluoxetine Hydrochloride) alone and who subsequently recovered. However, in an adult patient who took Flumusa (Fluoxetine Hydrochloride) alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established.

    Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving Flumusa (Fluoxetine Hydrochloride) alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of Flumusa (Fluoxetine Hydrochloride) daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal.

    Other important adverse reactions reported with Flumusa (Fluoxetine Hydrochloride) overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope.

    10.2 Animal Experience

    Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies.

    The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species.

    Among 6 dogs purposely overdosed with oral Flumusa (Fluoxetine Hydrochloride), 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically.

    In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose [see Overdosage (10.3)].

    10.3 Management of Overdose

    Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of Major Depressive Disorder.

    Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

    Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for Flumusa (Fluoxetine Hydrochloride) are known.

    A specific caution involves patients who are taking or have recently taken Flumusa (Fluoxetine Hydrochloride) and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Drug Interactions (7.9)].

    Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam.

    In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

    For specific information about overdosage with olanzapine and Flumusa (Fluoxetine Hydrochloride) in combination, refer to the Overdosage section of the olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules package insert.

    11 DESCRIPTION

    Flumusa (Fluoxetine Hydrochloride) capsules, USP are a selective serotonin reuptake inhibitor for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem ®, Flumusa (Fluoxetine Hydrochloride) hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the molecular formula of C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is:

    Flumusa (Fluoxetine Hydrochloride) hydrochloride, USP is a white to off-white crystalline powder. It is sparingly soluble in water and in dichloromethane, freely soluble in alcohol and in methanol, practically insoluble in ether.

    Each capsule contains Flumusa (Fluoxetine Hydrochloride) hydrochloride, USP equivalent to 40 mg (129.3 µmol) of Flumusa (Fluoxetine Hydrochloride). The 40 mg capsules also contain colloidal silicon dioxide, FD&C Blue No. 1, FD&C Yellow No. 6, gelatin, magnesium stearate, pregelatinized starch, titanium dioxide, and yellow iron oxide. The imprinting ink also contains D&C Yellow No. 10 aluminum lake, FD&C Blue No. 1 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, pharmaceutical glaze, propylene glycol, and synthetic black iron oxide.

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Although the exact mechanism of Flumusa is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin.

    12.2 Pharmacodynamics

    Studies at clinically relevant doses in man have demonstrated that Flumusa (Fluoxetine Hydrochloride) blocks the uptake of serotonin into human platelets. Studies in animals also suggest that Flumusa (Fluoxetine Hydrochloride) is a much more potent uptake inhibitor of serotonin than of norepinephrine.

    Antagonism of muscarinic, histaminergic, and α 1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Flumusa (Fluoxetine Hydrochloride) binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.

    12.3 Pharmacokinetics

    Systemic Bioavailability — In man, following a single oral 40 mg dose, peak plasma concentrations of Flumusa from 15 to 55 ng/mL are observed after 6 to 8 hours.

    Food does not appear to affect the systemic bioavailability of Flumusa (Fluoxetine Hydrochloride), although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, Flumusa (Fluoxetine Hydrochloride) may be administered with or without food.

    Protein Binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of Flumusa (Fluoxetine Hydrochloride) is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between Flumusa (Fluoxetine Hydrochloride) and other highly protein-bound drugs has not been fully evaluated, but may be important.

    Enantiomers — Flumusa (Fluoxetine Hydrochloride) is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state.

    Metabolism — Flumusa (Fluoxetine Hydrochloride) is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of Flumusa (Fluoxetine Hydrochloride). In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.

    Variability in Metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of Flumusa (Fluoxetine Hydrochloride). This explains how Flumusa (Fluoxetine Hydrochloride) achieves a steady-state concentration rather than increasing without limit.

    Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions (7.9)].

    Accumulation and Slow Elimination — The relatively slow elimination of Flumusa (Fluoxetine Hydrochloride) (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used [see Warnings and Precautions (5.12)]. After 30 days of dosing at 40 mg/day, plasma concentrations of Flumusa (Fluoxetine Hydrochloride) in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of Flumusa (Fluoxetine Hydrochloride) were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks.

    The long elimination half-lives of Flumusa (Fluoxetine Hydrochloride) and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with Flumusa (Fluoxetine Hydrochloride) and norfluoxetine following the discontinuation of Flumusa (Fluoxetine Hydrochloride).

    12.4 Specific Populations

    Liver Disease — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of Flumusa (Fluoxetine Hydrochloride). The elimination half-life of Flumusa (Fluoxetine Hydrochloride) was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of Flumusa (Fluoxetine Hydrochloride) in patients with liver disease must be approached with caution. If Flumusa (Fluoxetine Hydrochloride) is administered to patients with liver disease, a lower or less frequent dose should be used [see Dosage and Administration (2.7), Use in Specific Populations (8.6)].

    Renal Disease — In depressed patients on dialysis (N = 12), Flumusa (Fluoxetine Hydrochloride) administered as 20 mg once daily for 2 months produced steady-state Flumusa (Fluoxetine Hydrochloride) and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of Flumusa (Fluoxetine Hydrochloride) may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients.

    Geriatric Pharmacokinetics — The disposition of single doses of Flumusa (Fluoxetine Hydrochloride) in healthy elderly subjects (> 65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of Flumusa (Fluoxetine Hydrochloride) have been investigated in 260 elderly but otherwise healthy depressed patients (≥ 60 years of age) who received 20 mg Flumusa (Fluoxetine Hydrochloride) for 6 weeks. Combined Flumusa (Fluoxetine Hydrochloride) plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse reactions was observed in those elderly patients.

    Pediatric Pharmacokinetics (children and adolescents ) — Flumusa (Fluoxetine Hydrochloride) pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to < 13, 11 adolescents ages 13 to < 18) diagnosed with Major Depressive Disorder or Obsessive Compulsive Disorder (OCD). Flumusa (Fluoxetine Hydrochloride) 20 mg/day was administered for up to 62 days. The average steady-state concentrations of Flumusa (Fluoxetine Hydrochloride) in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in Flumusa (Fluoxetine Hydrochloride) pharmacokinetics was observed. Similar ranges of Flumusa (Fluoxetine Hydrochloride) and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to < 18) diagnosed with Major Depressive Disorder.

    Higher average steady-state Flumusa (Fluoxetine Hydrochloride) and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, Flumusa (Fluoxetine Hydrochloride) and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing.

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenicity — The dietary administration of Flumusa to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no evidence of carcinogenicity.

    Mutagenicity — Flumusa (Fluoxetine Hydrochloride) and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.

    Impairment of Fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that Flumusa (Fluoxetine Hydrochloride) had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with Flumusa (Fluoxetine Hydrochloride) [see Use in Specific Populations (8.4)].

    13.2 Animal Toxicology and/or Pharmacology

    Phospholipids are increased in some tissues of mice, rats, and dogs given Flumusa (Fluoxetine Hydrochloride) chronically. This effect is reversible after cessation of Flumusa (Fluoxetine Hydrochloride) treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown.

    14 CLINICAL STUDIES

    When using Flumusa and olanzapine in combination, also refer to the Clinical Studies section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules.

    14.1 Major Depressive Disorder

    Daily Dosing

    Adult — The efficacy of Flumusa (Fluoxetine Hydrochloride) was studied in 5- and 6-week placebo-controlled trials with depressed adult and geriatric outpatients (≥ 18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of Major Depressive Disorder. Flumusa (Fluoxetine Hydrochloride) was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Flumusa (Fluoxetine Hydrochloride) was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor.

    Two 6-week controlled studies (N = 671, randomized) comparing Flumusa (Fluoxetine Hydrochloride) 20 mg and placebo have shown Flumusa (Fluoxetine Hydrochloride) 20 mg daily to be effective in the treatment of elderly patients (≥ 60 years of age) with Major Depressive Disorder. In these studies, Flumusa (Fluoxetine Hydrochloride) produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤ 8. Flumusa (Fluoxetine Hydrochloride) was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between Flumusa (Fluoxetine Hydrochloride) (12%) and placebo (9%).

    A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤ 7 during each of the last 3 weeks of open-label treatment and absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on Flumusa (Fluoxetine Hydrochloride) 20 mg/day. These patients (N = 298) were randomized to continuation on double-blind Flumusa (Fluoxetine Hydrochloride) 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a modified HAMD-17 score of ≥ 14 for 3 weeks) was observed for patients taking Flumusa (Fluoxetine Hydrochloride) compared with those on placebo.

    Pediatric (children and adolescents) — The efficacy of Flumusa (Fluoxetine Hydrochloride) 20 mg/day in children and adolescents (N = 315 randomized; 170 children ages 8 to < 13, 145 adolescents ages 13 to ≤ 18) was studied in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of Major Depressive Disorder.

    In both studies independently, Flumusa (Fluoxetine Hydrochloride) produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo.

    Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender.

    14.2 Obsessive Compulsive Disorder

    Adult — The effectiveness of Flumusa for the treatment of Obsessive Compulsive Disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed Flumusa (Fluoxetine Hydrochloride) doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving Flumusa (Fluoxetine Hydrochloride) experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. In Study 2, patients receiving Flumusa (Fluoxetine Hydrochloride) experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined:

    Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies
    Flumusa (Fluoxetine Hydrochloride)
    Outcome Classification Placebo 20 mg 40 mg 60 mg
    Worse 8% 0% 0% 0%
    No change 64% 41% 33% 29%
    Minimally improved 17% 23% 28% 24%
    Much improved 8% 28% 27% 28%
    Very much improved 3% 8% 12% 19%
    Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

    Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients (N = 103 randomized; 75 children ages 7 to < 13, 28 adolescents ages 13 to < 18) with OCD (DSM-IV), patients received Flumusa (Fluoxetine Hydrochloride) 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. Flumusa (Fluoxetine Hydrochloride) produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS).

    Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender.

    14.3 Bulimia Nervosa

    The effectiveness of Flumusa (Fluoxetine Hydrochloride) for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of Flumusa (Fluoxetine Hydrochloride) or placebo in the morning. Patients in the 16-week study received a fixed Flumusa (Fluoxetine Hydrochloride) dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, Flumusa (Fluoxetine Hydrochloride) 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study. The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between Flumusa (Fluoxetine Hydrochloride) 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging.

    In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with Flumusa (Fluoxetine Hydrochloride) 60 mg/day, were randomized to continuation of Flumusa (Fluoxetine Hydrochloride) 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued Flumusa (Fluoxetine Hydrochloride) 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo.

    14.4 Panic Disorder

    The effectiveness of Flumusa (Fluoxetine Hydrochloride) in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia.

    Study 1 (N = 180 randomized) was a 12-week flexible-dose study. Flumusa (Fluoxetine Hydrochloride) was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively.

    Study 2 (N = 214 randomized) was a 12-week flexible-dose study. Flumusa (Fluoxetine Hydrochloride) was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively.

    16 HOW SUPPLIED/STORAGE AND HANDLING

    16.1 How Supplied

    Flumusa Capsules, USP 40mg * are green opaque cap with orange opaque body, hard gelatin #2 capsules filled with white to off-white powder, imprinted with "RX632" on the cap and body in black ink.  They are available as follows:

    Bottle of 30  NDC: 35356-729-30

    16.2 Storage and Handling

    Store at 20 - 25° C (68 - 77° F).

    17 PATIENT COUNSELING INFORMATION

    See the FDA-approved Medication Guide.

    Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Flumusa capsules, USP as monotherapy or in combination with olanzapine. When using Flumusa (Fluoxetine Hydrochloride) capsules, USP and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules.

    17.1 General Information

    Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with Flumusa (Fluoxetine Hydrochloride) capsules, USP and to reread it each time the prescription is renewed.

    Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Flumusa (Fluoxetine Hydrochloride) capsules, USP and should counsel them in its appropriate use. Healthcare providers should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

    Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking Flumusa (Fluoxetine Hydrochloride) capsules, USP.

    When using Flumusa (Fluoxetine Hydrochloride) capsules, USP and olanzapine in combination, also refer to the Medication Guide for olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules.

    17.2 Clinical Worsening and Suicide Risk

    Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Box Warning and Warnings and Precautions (5.1)].

    17.3 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions

    Patients should be cautioned about the risk of serotonin syndrome or NMS-like reactions with the concomitant use of Flumusa (Fluoxetine Hydrochloride) capsules, USP and triptans, tramadol, or other serotonergic agents [see Warnings and Precautions (5.2) and Drug Interactions (7.3)].

    Patients should be advised of the signs and symptoms associated with serotonin syndrome or NMS-like reactions that may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, in which the symptoms may include hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be cautioned to seek medical care immediately if they experience these symptoms.

    17.4 Allergic Reactions and Rash

    Patients should be advised to notify their physician if they develop a rash or hives [see Warnings and Precautions ]. Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms.

    17.5 Abnormal Bleeding

    Patients should be cautioned about the concomitant use of Flumusa (Fluoxetine Hydrochloride) and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding [see Warnings and Precautions (5.7) and Drug Interactions (7.6)]. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking Flumusa (Fluoxetine Hydrochloride) capsules, USP.

    17.6 Hyponatremia

    Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including Flumusa capsules, USP. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see Warnings and Precautions (5.8)].

    17.7 Potential for Cognitive and Motor Impairment

    Flumusa (Fluoxetine Hydrochloride) capsules, USP may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected [see Warnings and Precautions (5.11)].

    17.8 Use of Concomitant Medications

    Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Symbyax ® hydrochloride capsules), Sarafem® (fluoxetine capsules), or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on Flumusa (Fluoxetine Hydrochloride) capsules, USP.

    17.9 Discontinuation of Treatment

    Patients should be advised to take Flumusa (Fluoxetine Hydrochloride) capsules, USP exactly as prescribed, and to continue taking Flumusa (Fluoxetine Hydrochloride) capsules, USP as prescribed even after their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking Flumusa (Fluoxetine Hydrochloride) capsules, USP without consulting their physician [see Warnings and Precautions (5.13)]. Patients should be advised to consult with their healthcare provider if their symptoms do not improve with Flumusa (Fluoxetine Hydrochloride) capsules, USP.

    17.10 Use in Specific Populations

    Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Flumusa capsules, USP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].

    Nursing Mothers — Patients should be advised to notify their physician if they intend to breast-feed an infant during therapy. Because Flumusa (Fluoxetine Hydrochloride) is excreted in human milk, nursing while taking Flumusa (Fluoxetine Hydrochloride) capsules, USP is not recommended [see Use in Specific Populations (8.3)].

    Pediatric Use — Flumusa (Fluoxetine Hydrochloride) capsules, USP is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1)]. Limited evidence is available concerning the longer-term effects of Flumusa (Fluoxetine Hydrochloride) on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving Flumusa (Fluoxetine Hydrochloride). Safety and effectiveness of Flumusa (Fluoxetine Hydrochloride) capsules, USP and olanzapine in combination in patients less than 18 years of age have not been established [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)].

    MEDICATION GUIDE

    Flumusa (Fluoxetine Hydrochloride) CAPSULES, USP

    Rx only

    Read the Medication Guide that comes with Flumusa (Fluoxetine Hydrochloride) capsules, USP before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.

    What is the most important information I should know about Flumusa (Fluoxetine Hydrochloride) capsules, USP?

    Flumusa (Fluoxetine Hydrochloride) capsules, USP and other antidepressant medicines may cause serious side effects, including:

    1. Suicidal thoughts or actions:

    • Flumusa (Fluoxetine Hydrochloride) capsules, USP and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.
    • Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.
    • Watch for these changes and call your healthcare provider right away if you notice:
      • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
      • Pay particular attention to such changes when Flumusa (Fluoxetine Hydrochloride) capsules, USP is started or when the dose is changed.
    Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

    Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:

    • attempts to commit suicide
    • acting on dangerous impulses
    • acting aggressive or violent
    • thoughts about suicide or dying
    • new or worse depression
    • new or worse anxiety or panic attacks
    • feeling agitated, restless, angry or irritable
    • trouble sleeping
    • an increase in activity or talking more than what is normal for you
    • other unusual changes in behavior or mood
    Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Flumusa (Fluoxetine Hydrochloride) capsules, USP may be associated with these serious side effects:

    2. Serotonin Syndrome or Neuroleptic Malignant Syndrome-like reactions. This condition can be life-threatening and may include:

    • agitation, hallucinations, coma or other changes in mental status
    • coordination problems or muscle twitching (overactive reflexes)
    • racing heartbeat, high or low blood pressure
    • sweating or fever
    • nausea, vomiting, or diarrhea
    • muscle rigidity
    3. Severe allergic reactions:

    • trouble breathing
    • swelling of the face, tongue, eyes or mouth
    • rash, itchy welts (hives) or blisters, alone or with fever or joint pain
    4. Abnormal bleeding: Flumusa (Fluoxetine Hydrochloride) capsules, USP and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

    5. Seizures or convulsions

    6. Manic episodes:

    • greatly increased energy
    • severe trouble sleeping
    • racing thoughts
    • reckless behavior
    • unusually grand ideas
    • excessive happiness or irritability
    • talking more or faster than usual
    7. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment.

    8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:

    • headache
    • weakness or feeling unsteady
    • confusion, problems concentrating or thinking or memory problems
    Do not stop Flumusa (Fluoxetine Hydrochloride) capsules, USP without first talking to your healthcare provider. Stopping Flumusa (Fluoxetine Hydrochloride) capsules, USP too quickly may cause serious symptoms including:

    • anxiety, irritability, high or low mood, feeling restless or changes in sleep habits
    • headache, sweating, nausea, dizziness
    • electric shock-like sensations, shaking, confusion
    What are Flumusa (Fluoxetine Hydrochloride) capsules, USP?

    Flumusa (Fluoxetine Hydrochloride) capsules, USP are a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider.

    Flumusa (Fluoxetine Hydrochloride) capsules, USP are used to treat:

    • Major Depressive Disorder (MDD)
    • Obsessive Compulsive Disorder (OCD)
    • Bulimia Nervosa*
    • Panic Disorder*
    • Depressive episodes associated with Bipolar I Disorder, taken with olanzapine (Zyprexa)*
    *Not approved for use in children

    Talk to your healthcare provider if you do not think that your condition is getting better with Flumusa (Fluoxetine Hydrochloride) capsules, USP treatment.

    Who should not take Flumusa (Fluoxetine Hydrochloride) capsules, USP?

    Do not take Flumusa (Fluoxetine Hydrochloride) capsules, USP if you:

    • are allergic to Flumusa (Fluoxetine Hydrochloride) hydrochloride, USP or any of the ingredients in Flumusa (Fluoxetine Hydrochloride) capsules, USP. See the end of this Medication Guide for a complete list of ingredients in Flumusa (Fluoxetine Hydrochloride) capsules, USP.
    • take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI.
      • Do not take an MAOI within 5 weeks of stopping Flumusa (Fluoxetine Hydrochloride) capsules, USP.
      • Do not start Flumusa (Fluoxetine Hydrochloride) capsules, USP if you stopped taking an MAOI in the last 2 weeks.
    People who take Flumusa (Fluoxetine Hydrochloride) capsules, USP close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:

    • high fever
    • uncontrolled muscle spasms
    • stiff muscles
    • rapid changes in heart rate or blood pressure
    • confusion
    • loss of consciousness (pass out)
    • take Mellaril® (thioridazine). Do not take Mellaril® within 5 weeks of stopping Flumusa (Fluoxetine Hydrochloride) capsules, USP because this can cause serious heart rhythm problems or sudden death.
    • take the antipsychotic medicine pimozide (Orap®) because this can cause serious heart problems.
    What should I tell my healthcare provider before taking Flumusa (Fluoxetine Hydrochloride) capsules, USP? Ask if you are not sure.

    Before starting Flumusa (Fluoxetine Hydrochloride) capsules, USP, tell your healthcare provider if you:

    • Are taking certain drugs or treatments such as:
      • Triptans used to treat migraine headache
      • Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, MAOI's (including linezolid, an antibiotic), or antipsychotics
      • Tramadol
      • Over-the-counter supplements such as tryptophan or St. John's Wort
      • Electroconvulsive therapy (ECT)
    • have liver problems
    • have kidney problems
    • have heart problems
    • have or had seizures or convulsions
    • have bipolar disorder or mania
    • have low sodium levels in your blood
    • have a history of a stroke
    • have high blood pressure
    • have or had bleeding problems
    • are pregnant or plan to become pregnant. It is not known if Flumusa (Fluoxetine Hydrochloride) capsules, USP will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy.
    • are breast-feeding or plan to breast-feed. Some Flumusa (Fluoxetine Hydrochloride) may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Flumusa (Fluoxetine Hydrochloride) capsules, USP.
    Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Flumusa (Fluoxetine Hydrochloride) capsules, USP and some medicines may interact with each other, may not work as well, or may cause serious side effects.

    Your healthcare provider or pharmacist can tell you if it is safe to take Flumusa (Fluoxetine Hydrochloride) capsules, USP with your other medicines. Do not start or stop any medicine while taking Flumusa (Fluoxetine Hydrochloride) capsules, USP without talking to your healthcare provider first.

    If you take Flumusa (Fluoxetine Hydrochloride) capsules, USP, you should not take any other medicines that contain Flumusa (Fluoxetine Hydrochloride) hydrochloride including:

    • Symbyax® (olanzapine and Flumusa (Fluoxetine Hydrochloride) hydrochloride capsules)
    • Sarafem® (fluoxetine hydrochloride capsules)
    • PROZAC® Weekly
    How should I take Flumusa (Fluoxetine Hydrochloride) capsules, USP?

    • Take Flumusa (Fluoxetine Hydrochloride) capsules, USP exactly as prescribed. Your healthcare provider may need to change the dose of Flumusa (Fluoxetine Hydrochloride) capsules, USP until it is the right dose for you.
    • Flumusa (Fluoxetine Hydrochloride) capsules, USP may be taken with or without food.
    • If you miss a dose of Flumusa (Fluoxetine Hydrochloride) capsules, USP, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Flumusa (Fluoxetine Hydrochloride) capsules, USP at the same time.
    • If you take too much Flumusa (Fluoxetine Hydrochloride) capsules, USP, call your healthcare provider or poison control center right away, or get emergency treatment.
    What should I avoid while taking Flumusa (Fluoxetine Hydrochloride) capsules, USP?

    Flumusa (Fluoxetine Hydrochloride) capsules, USP can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how Flumusa (Fluoxetine Hydrochloride) capsules, USP affects you. Do not drink alcohol while using Flumusa (Fluoxetine Hydrochloride) capsules, USP.

    What are the possible side effects of Flumusa (Fluoxetine Hydrochloride) capsules, USP?

    Flumusa (Fluoxetine Hydrochloride) capsules, USP may cause serious side effects, including:

    • See “What is the most important information I should know about Flumusa (Fluoxetine Hydrochloride) capsules, USP?”
    • Problems with blood sugar control. People who have diabetes and take Flumusa (Fluoxetine Hydrochloride) capsules, USP may have problems with low blood sugar while taking Flumusa (Fluoxetine Hydrochloride) capsules, USP. High blood sugar can happen when Flumusa (Fluoxetine Hydrochloride) capsules, USP is stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking Flumusa (Fluoxetine Hydrochloride) capsules, USP.
    • Feeling anxious or trouble sleeping
    Common possible side effects in people who take Flumusa (Fluoxetine Hydrochloride) capsules, USP include:

    • unusual dreams
    • sexual problems
    • loss of appetite, diarrhea, indigestion, nausea or vomiting, weakness, or dry mouth
    • flu symptoms
    • feeling tired or fatigued
    • change in sleep habits
    • yawning
    • sinus infection or sore throat
    • tremor or shaking
    • sweating
    • feeling anxious or nervous
    • hot flashes
    • rash
    Other side effects in children and adolescents include:

    • increased thirst
    • abnormal increase in muscle movement or agitation
    • nose bleed
    • urinating more often
    • heavy menstrual periods
    • possible slowed growth rate and weight change. Your child's height and weight should be monitored during treatment with Flumusa (Fluoxetine Hydrochloride) capsules, USP.
    Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Flumusa (Fluoxetine Hydrochloride) capsules, USP. For more information, ask your healthcare provider or pharmacist.

    Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

    How should I store Flumusa (Fluoxetine Hydrochloride) capsules, USP?

    • Store Flumusa (Fluoxetine Hydrochloride) capsules, USP at room temperature between 68 - 77° F (20 - 25° C).
    • Keep Flumusa (Fluoxetine Hydrochloride) capsules, USP away from light.
    • Keep Flumusa (Fluoxetine Hydrochloride) capsules, USP bottle closed tightly.
    Keep Flumusa (Fluoxetine Hydrochloride) capsules, USP and all medicines out of the reach of children.

    General information about Flumusa (Fluoxetine Hydrochloride) capsules, USP

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Flumusa (Fluoxetine Hydrochloride) capsules, USP for a condition for which it was not prescribed. Do not give Flumusa (Fluoxetine Hydrochloride) capsules, USP to other people, even if they have the same condition. It may harm them.

    This Medication Guide summarizes the most important information about Flumusa (Fluoxetine Hydrochloride) capsules, USP. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about Flumusa (Fluoxetine Hydrochloride) capsules, USP that is written for healthcare professionals.

    For more information about Flumusa (Fluoxetine Hydrochloride) capsules, USP call 1-888-Ranbaxy (726-2299).

    What are the ingredients in Flumusa (Fluoxetine Hydrochloride) capsules, USP?

    Active ingredient: Flumusa (Fluoxetine Hydrochloride) hydrochloride, USP

    Inactive ingredients: colloidal silicon dioxide, FD&C Blue No. 1, FD&C Yellow No. 6, gelatin, magnesium stearate, pregelatinized starch, titanium dioxide, and yellow iron oxide. The imprinting ink also contains D&C Yellow No. 10 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, FD&C Blue No. 1 aluminum lake, pharmaceutical glaze, propylene glycol, and synthetic black iron oxide.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    Manufactured for:

    Ranbaxy Pharmaceuticals Inc.

    Jacksonville, FL 32257 USA

    August 2011

    Mellaril ® is a registered trademark of Novartis AG Corporation.

    Orap ® is a registered trademark of Teva Pharmaceuticals USA.

    Prozac ® Weekly is a trademark of Eli Lilly and Company.

    Sarafem ® and Symbyax® are registered trademarks of Eli Lilly and Company.

    Zyprexa ® is a trademark of Eli Lilly and Company.

    Coumadin ® is a trademark of Bristol Myers Squibb.

    Jantoven ® is a trademark of USL Pharma.


    Flumusa pharmaceutical active ingredients containing related brand and generic drugs:

    infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


    Flumusa available forms, composition, doses:

    infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
    Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
    Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


    Flumusa destination | category:

    infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
    Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


    Flumusa Anatomical Therapeutic Chemical codes:

    infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


    Flumusa pharmaceutical companies:

    infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
    Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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    Frequently asked Questions

    Can i drive or operate heavy machine after consuming Flumusa?

    Depending on the reaction of the Flumusa after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Flumusa not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

    Is Flumusa addictive or habit forming?

    Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

    Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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    Review

    sDrugs.com conducted a study on Flumusa, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Flumusa consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

    Visitor reports

    Visitor reported useful

    No survey data has been collected yet


    Visitor reported side effects

    No survey data has been collected yet


    One visitor reported price estimates

    What is your opinion about drug cost? Did you feel the cost is apt, or did you feel it is expensive?
    The report given by the sDrugs.com website users shows the following figures about several people who felt the medicine Flumusa is expensive, and the medicine is not expensive. The results are mixed. The perception of the cost of the medicine to be expensive or not depends on the brand name of the medicine, country, and place where it is sold, and the affordability of the patient. You can choose a generic drug in the place of the branded drug to save the cost. The efficiency of the medicine will not vary if it is generic or a branded one.
    Visitors%
    Not expensive1
    100.0%


    Visitor reported frequency of use

    No survey data has been collected yet


    Visitor reported doses

    No survey data has been collected yet


    Visitor reported time for results

    No survey data has been collected yet


    Visitor reported administration

    No survey data has been collected yet


    One visitor reported age

    Visitors%
    30-451
    100.0%


    Visitor reviews


    There are no reviews yet. Be the first to write one!


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    The information was verified by Dr. Arunabha Ray, MD Pharmacology

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