DRUGS & SUPPLEMENTS
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Medication: Flumusa

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

    Dosage and administration

    Individual. It is recommended to use the minimum effective dose of Flumusa Sandoz. 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.

    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 alprazolam.

    The simultaneous use with hormonal oral contraceptives increased T1/2 of 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 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. WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
    2. 1       INDICATIONS AND USAGE
    3. 2       DOSAGE   AND   ADMINISTRATION
    4. 3       DOSAGE   FORMS   AND   STRENGTHS
    5. 4       CONTRAINDICATIONS
    6. 5       WARNINGS   AND   PRECAUTIONS
    7. 6       ADVERSE   REACTIONS
    8. 7       DRUG   INTERACTIONS
    9. 8       USE   IN   SPECIFIC   POPULATIONS
    10. 9       DRUG   ABUSE   AND   DEPENDENCE
    11. 10       OVERDOSAGE
    12. 11       DESCRIPTION
    13. 13       NONCLINICAL   TOXICOLOGY
    14. 14       CLINICAL   STUDIES
    15. 16       HOW   SUPPLIED/STORAGE   AND   HANDLING
    16. 17       PATIENT   COUNSELING   INFORMATION

    WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS


    Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short - term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of SARAFEM or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SARAFEM is not approved for use in pediatric patients [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4) ].

    WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS

    See full prescribing information for complete boxed warning.

    Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for Major Depressive Disorder (MDD) and other psychiatric disorders. SARAFEM is not approved for use in pediatric patients ( 5.1 ).

    1       INDICATIONS AND USAGE


    SARAFEM is a selective serotonin reuptake inhibitor  indicated for the treatment of Premenstrual Dysphoric Disorder (PMDD) 

    1.1       Premenstrual   Dysphoric   Disorder   (PMDD)


    SARAFEM is indicated for the treatment of premenstrual dysphoric disorder (PMDD) [see   Clinical Studies (14.1) ].  

    The effectiveness of SARAFEM in long-term use (that is, for more than 6 months) has not been systematically evaluated in placebo-controlled trials. The use of SARAFEM for extended periods should be periodically re-evaluated for the individual patient [see   Dosage and Administration (2.1) ].

    2       DOSAGE   AND   ADMINISTRATION

    • 20 mg/day continuously or intermittently 

    2.1       Treatment


    The recommended dose of SARAFEM for the treatment of PMDD is 20 mg/day given continuously or intermittently (defined as starting a daily dose 14 days prior to the anticipated onset of menstruation through the first full day of menses and repeating with each new cycle). The dosing regimen should be based on individual patient characteristics. In a study comparing continuous dosing of Flumusa (Fluoxetine Hydrochloride) 20 and 60 mg/day to placebo, both doses were proven to be effective, but there was no statistically significant added benefit for the 60 mg/day compared with the 20 mg/day dose. Flumusa (Fluoxetine Hydrochloride) doses above 60 mg/day have not been systematically studied in patients with PMDD. The maximum Flumusa (Fluoxetine Hydrochloride) dose should not exceed 80 mg/day [see Clinical Studies (14.1) ].

    Systematic evaluation of SARAFEM has shown that its efficacy in PMDD is maintained for periods of up to 6 months at a dose of 20 mg/day given continuously and up to 3 months at a dose of 20 mg/day given intermittently [see   Clinical Studies (14.1) ]. Patients should be periodically re-assessed to determine the need for continued treatment.

    2. 2       Dosing   in   Specific   Populations


    Treatment   of   Pregnant   Women  — PMDD does not exist in pregnancy. However, if there is a need to treat pregnant women with fluoxetine, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding [see Use in Specific Populations (8.1) ].

    Hepatic   Impairment — A lower or less frequent dosage should be used in patients with hepatic impairment  [see   Clinical Pharmacology (12.3)   and   Use in Specific Populations (8.6) ].

    Concomitant   Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [ see   Warnings and Precautions (5.11) and Clinical Pharmacology (12.3) ].

    2. 3       Discontinuation   of   Treatment  


    Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [ see   Warnings and Precautions ].

    2.4       Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders


    At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with SARAFEM. Conversely, at least 5 weeks should be allowed after stopping SARAFEM before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1) ].

    2.5       Use of SARAFEM with Other MAOIs such as Linezolid or Methylene Blue


    Do not start SARAFEM in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1) ].

    In some cases, a patient already receiving SARAFEM therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, SARAFEM should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with SARAFEM may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2) ].

    The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with SARAFEM is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2) ].

    3       DOSAGE   FORMS   AND   STRENGTHS

    • 10 mg tablet is a cream, round tablet embossed with S10 on one side.
    • 15 mg tablet is a white, round tablet embossed with S15 on one side.
    • 20 mg tablet is a yellow, round tablet embossed with S20 on one side.
    • Tablets: 10 mg, 15 mg, 20 mg 

    4       CONTRAINDICATIONS

    • Serotonin Syndrome and MAOIs: Do not use with MAOIs intended to treat psychiatric disorders with SARAFEM or within 5 weeks of stopping treatment with SARAFEM. Do not use SARAFEM within 14 days of stopping an MAIO intended to treat psychiatric disorders. In addition, do not start SARAFEM in a patient who is being treated with linezolid or intravenous methylene blue
    • Do not use with pimozide due to risk of drug interaction or QTc prolongation 
    • 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 SARAFEM

    4.1       Monoamine   Oxidase   Inhibitors  


    The use of MAOIs intended to treat psychiatric disorders with SARAFEM or within 5 weeks of stopping treatment with SARAFEM is contraindicated because of an increased risk of serotonin syndrome. The use of SARAFEM within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [se e Dosage and Administration  and Warnings and Precautions (5.2) ].

    Starting SARAFEM in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.5) and Warnings and Precautions (5.2) ].

    4.2       Other Contraindications


    The use of SARAFEM is contraindicated with the following:

    • Pimozide [see   Drug Interactions (7.9) ]
    • Thioridazine [see   Drug Interactions (7.9) ]

    5       WARNINGS   AND   PRECAUTIONS

    • Clinical   Worsening   and   Suicide   Risk: Monitor for clinical worsening and suicidal thinking and behavior 
    • Serotonin   Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including SARAFEM, both when taken alone, but especially when co-administered with other serotonergic agents. If such symptoms occur, discontinue SARAFEM and initiate supportive treatment. If concomitant use of SARAFEM with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk of serotonin syndrome, particularly during treatment initiation and dose increases
    • Allergic   Reactions   and   Rash: Discontinue upon appearance of rash or allergic phenomena 
    • Activation   of   Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania 
    • Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold 
    • Altered   Appetite   and   Weight: Significant weight loss has occurred 
    • 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
    • Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients who have untreated anatomically narrow angles and who are treated with antidepressants
    • Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH) 
    • Anxiety   and   Insomnia: May occur 
    • Potential   for   Cognitive   and   Motor   Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery 
    • Long   Half-Life: Changes in dose will not be fully reflected in plasma for several weeks 

         

    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 1.

    Age   Range Drug-Placebo D ifference in Number of
    Cases of Suicidality per 1000 Patients Treated
    Increases Compared to Placebo
    <18 14 additional cases
    18-24 5 additional cases
    Decreases Compared to Placebo
    25-64 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, that is, 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 (5.14) ].

    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 SARAFEM should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

    It should be noted that SARAFEM is not approved for treating any indication in the pediatric population.

    5.2       Serotonin   Syndrome  


    The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including SARAFEM, alone but particularly with concomitant use of other serotonergic drugs and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

    Serotonin syndrome symptoms may include mental status changes (for example, agitation, hallucinations, delirium, and coma), autonomic instability (for example, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (for example, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (for example, nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

    The concomitant use of SARAFEM with MAOIs intended to treat psychiatric disorders is contraindicated. SARAFEM should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking SARAFEM. SARAFEM should be discontinued before initiating treatment with the MAOI [see Contraindications (4.1) and Dosage and Administration (2.5) ].

    If concomitant use of SARAFEM with other serotonergic drugs, that is, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

    Treatment with SARAFEM and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

    5.3       Allergic   Reactions   and   Rash


    In 4 clinical trials for PMDD, 4% of 415 patients treated with SARAFEM reported rash and/or urticaria. None of these cases were classified as serious and 2 of 415 patients (both receiving 60 mg) were withdrawn from treatment because of rash and/or urticaria.

    In US Flumusa (Fluoxetine Hydrochloride) clinical trials for conditions other than PMDD, 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 for conditions other than PMDD, 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 fluoxetine, 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, SARAFEM 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 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 SARAFEM is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

    No patients treated with SARAFEM in 4 PMDD clinical trials (N = 415) reported mania/hypomania. In all US Flumusa (Fluoxetine Hydrochloride) clinical trials for conditions other than PMDD, 0.7% of 10,782 patients reported mania/hypomania. Activation of mania/hypomania may occur with medications used to treat depression, especially in patients predisposed to Bipolar I Disorder.

    5.5       Seizures


    No patients treated with SARAFEM in 4 PMDD clinical trials (N = 415) reported seizures. In all US fluoxetine clinical trials for conditions other than PMDD, 0.2% of 10,782 patients reported convulsions. SARAFEM should be introduced with care in patients with a history of seizures.

    5.6       Altered   Appetite   and   Weight


    In 2 placebo-controlled clinical trials for PMDD, patients treated with SARAFEM reported changes in appetite and weight [see Table 2]. For individual rates for SARAFEM 20 mg given as continuous and intermittent dosing, see Table 4 and accompanying footnote [see Adverse Reactions ].

    Percentage   of   Patients   Reporting   Adverse Reaction
    Treatment   Emergent
    Adverse   Reaction
    20   mg   (continuous   and
    intermittent   pooled)
    60   mg   (continuous) Placebo   (pooled)
    Anorexia (decreased
    appetite)
    4% 13% 2%
    Weight Loss (>7%) 7% 12% 3%
    Weight Gain (>7%) 8% 6% 1%

         

    In US placebo-controlled clinical trials of fluoxetine for other approved indications, changes in appetite and weight have also been reported [see   Adverse Reactions (6.1)   Table   5 ].  

    5.7       Abnormal   Bleeding


    SNRIs and SSRIs, including fluoxetine, 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       Angle-Closure Glaucoma


    The pupillary dilation that occurs following use of many antidepressants and SARAFEM may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

    5.9       Hyponatremia


    Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion. 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 SARAFEM 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. 10       Anxiety   and   Insomnia


    In 2 placebo-controlled clinical trials for PMDD, patients treated with SARAFEM reported anxiety, nervousness, and insomnia  [see   Table   3 ].

    For individual rates of anxiety, nervousness, and insomnia with SARAFEM 20 mg given as continuous or intermittent dosing, see Table 5 and accompanying footnote [see   Adverse Reactions (6.1) ].

    Percentage   of   Patients   Reporting   Adverse Reaction
    Treatment
    Emergent   Adverse
    Reaction
    20   mg   (continuous
    and   intermittent
    pooled)
    60   mg   (continuous) Placebo   (pooled)
    Anxiety 3% 9% 4%
    Nervousness 5% 9% 3%
    Insomnia 9% 26% 7%

    Anxiety, nervousness, and insomnia were associated with discontinuation for SARAFEM [see   Table   4   and   Warnings and Precautions (5.14) ].

    Percentage   of   Patient   Discontinuation due to Adverse Reaction
    Treatment
    Emergent   Adverse
    Reaction
    20   mg   (continuous
    and   intermittent
    pooled)
    60   mg   (continuous) Placebo   (pooled)
    Anxiety 0% 6% 1%
    Nervousness 1% 0% 0.5%
    Insomnia 1% 4% 0.5%

    In US placebo-controlled clinical trials of fluoxetine for other approved indications, anxiety, nervousness, and insomnia have been among the most commonly reported adverse reactions [see   Table   6   and   Adverse Reactions (6.1) ].

    5.1 1       Use   in   Patients   with   Concomitant   Illness


    Clinical experience with Flumusa 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, for a condition other than PMDD, 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 fluoxetine, 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.

    5.1 2       Potential   for   Cognitive   and   Motor   Impairment


    SARAFEM 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.

    5.1 3       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 and norfluoxetine following the discontinuation of Flumusa (Fluoxetine Hydrochloride) [see Clinical Pharmacology (12.3) and Drug Interactions (7) ].

    5.1 4       Discontinuation   of   Treatment  


    During marketing of SARAFEM, 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 (for example, 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 SARAFEM. 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 dose may continue to be decreased 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.

    6       ADVERSE   REACTIONS


    Most common adverse reactions associated with SARAFEM 20 mg (either continuous or intermittent) for PMDD:

    Headache, asthenia, pain, accidental injury, infection, flu syndrome, nausea, diarrhea, insomnia, dizziness, nervousness, thinking abnormal, libido decreased, rhinitis, and pharyngitis.



    To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-433-8871 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) have been administered to 10,782 patients with various diagnoses in US 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 (that is, 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 placebo - controlled PMDD clinical trials — In 1 of 3 placebo-controlled, continuous-dosing trials and 1 placebo-controlled, intermittent-dosing trial of Flumusa (Fluoxetine Hydrochloride) in PMDD, treatment-emergent adverse reactions reporting rates were assessed. The information contained in Table 5 enumerates the most common treatment-emergent adverse reactions associated with the use of SARAFEM 20 mg (incidence of at least 5% for SARAFEM 20 mg and greater than placebo) for the treatment of PMDD and is based on data from the continuous-dosing trial at the recommended dose of SARAFEM (SARAFEM 20 mg, N = 104; placebo, N = 108) and data from the intermittent-dosing trial of Flumusa (Fluoxetine Hydrochloride) in PMDD (SARAFEM 20 mg, N = 86; placebo, N = 88).

    Percentage   of   Patients   Reporting   Adverse R eaction
     Body   System/Adverse   Reaction 1 SARAFEM
    20
      mg/day
    Continuously

      (N   =   104)
    SARAFEM
    20
      mg/day
    Intermittently

      (N   =   86)
    Placebo
      (Pooled)
     
    (N
      =   196)
     Body   as   a   Whole
       Headache 13 15 11
       Asthenia 12 8 4
       Pain 9 3 7
       Accidental injury 8 1 5
       Infection 7 0 3
       Flu syndrome 12 3 7
     Digestive   System
       Nausea 13 9 6
       Diarrhea 6 2 6
     Nervous   System
       Insomnia 9 10 7
       Dizziness 7 2 3
       Nervousness 7 3 3
      Thinking abnormal2 6 5 0
       Libido decreased 3 9 1
     Respiratory   System
       Rhinitis 23 16 15
       Pharyngitis 10 6 5

    1       Included in the table are adverse reactions reported by at least 5% of patients taking SARAFEM 20 mg either continuously or intermittently. For additional adverse reaction terms referenced in Warnings and Precautions, reporting rates for SARAFEM 20 mg continuous and intermittent were, respectively: anxiety 4.8%, 1.2% and anorexia 3.8%, 3.5%.

    2       Thinking abnormal is the COSTART term that captures concentration difficulties.

    Incidence in US depression, OCD, and bulimia placebo - controlled clinical trials (excluding data from extensions of trials) — Table 6 enumerates the most common treatment-emergent adverse reactions associated with the use of Flumusa (Fluoxetine Hydrochloride) up to 80 mg (incidence of at least 2% for Flumusa (Fluoxetine Hydrochloride) and greater than placebo) in female patients ages 18 to 45 years from US placebo-controlled clinical trials in the treatment of depression, OCD, and bulimia.

    Percentage   of   Patients   Reporting Adverse Reaction
     Body System/Adverse Reaction 1 Fluoxetine   (N   =   1145) Placebo   (N   =   553)
     Body   as   a   Whole
        Headache 24 21
        Asthenia 14 6
        Flu syndrome 7 3
        Abdominal pain 6 5
        Accidental injury 4 3
        Fever 3 2
    Cardiovascular   System
       Palpitation 3 2
       Vasodilatation 3 1
     Digestive   System  
       Nausea 27 11
       Anorexia 11 4
       Dry mouth  11 8
       Diarrhea 10 7
       Dyspepsia 7 5
       Constipation 5 3
       Vomiting 3 2
     Metabolic   and   Nutritional
      Disorders
       Weight loss 3 1
     Nervous   System
       Insomnia 24 11
       Nervousness 14 10
       Anxiety 13 9
       Somnolence 13 6
       Tremor 12 1
       Dizziness 11 5
       Libido decreased 4 1
       Abnormal dreams 3 2
      Thinking abnormal2 3 2
     Respiratory   System
       Pharyngitis 6 5
       Yawn 5 --
     Skin   and   Appendages   Skin   and
     Subcutaneous   Tissue   Disorders
       Sweating  8 3
       Rash 5 3
     Special   Senses
       Abnormal vision 3 1
     Urogenital   System
       Urinary frequency 2 1

    1       Included are reactions reported by at least 2% of patients taking fluoxetine, except the following adverse reactions, which had an incidence on placebo greater than Flumusa (Fluoxetine Hydrochloride) (depression, OCD, and bulimia combined): back pain, cough increased, depression (includes suicidal thoughts), dysmenorrhea, flatulence, infection, myalgia, pain, pruritus, rhinitis, sinusitis.

    2       Thinking abnormal is the COSTART term that captures concentration difficulties.

             Incidence less than 0.5%.

    Adverse reactions associated with discontinuation in two placebo - controlled PMDD clinical trials — In a continuous-dosing PMDD placebo-controlled trial, the most common adverse reaction (incidence at least 2% for SARAFEM 20 mg and greater than placebo) associated with discontinuation was nausea (3% for SARAFEM 20 mg, N = 104 and 1% for placebo, N = 108). In an intermittent-dosing placebo-controlled trial, no reactions associated with discontinuation reached an incidence of 2% for SARAFEM 20 mg. In these clinical trials, more than one reaction may have been recorded as the cause of discontinuation.

    Adverse reactions associated with discontinuation in depression, OCD, and bulimia placebo - controlled US clinical trials (excluding data from extensions of trials) — In female patients age 18 to 45 years in US depression, OCD, and bulimia placebo-controlled clinical trials combined, which collected a single primary reaction associated with discontinuation (incidence at least 1% for Flumusa (Fluoxetine Hydrochloride) and at least twice that for placebo), insomnia (1%, N = 561) was the only reaction reported.

    Female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a mood-related 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. For example, in women (age 18 to 45) receiving Flumusa (Fluoxetine Hydrochloride) for indications other than PMDD, decreased libido was seen at an incidence of 4% for Flumusa (Fluoxetine Hydrochloride) compared with 1% for placebo. There have been spontaneous reports in women (age 18 to 45) taking Flumusa (Fluoxetine Hydrochloride) for indications other than PMDD of orgasmic dysfunction, including anorgasmia.

    There are no adequate and well-controlled studies examining sexual dysfunction with Flumusa (Fluoxetine Hydrochloride) treatment. 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 all treatment-emergent adverse reactions reported at anytime by females and males taking Flumusa in all US clinical trials for conditions other than PMDD as of May 8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 1 or 5 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those adverse reactions for which a causal relationship to Flumusa (Fluoxetine Hydrochloride) use was considered remote; (4) adverse reactions occurring in only 1 patient treated with Flumusa (Fluoxetine Hydrochloride) and which did not have a substantial probability of being acutely life-threatening; and (5) adverse reactions that could only occur in males.

    Adverse reactions are classified within body system categories using the following definitions: frequent adverse reactions are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in less than 1/1000 patients.

    Body as a WholeFrequent: chest pain and chills; Infrequent: face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, hypothermia, intentional injury, photosensitivity reaction.

    Cardiovascular SystemFrequent: hypertension; Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, vascular headache; Rare: bradycardia, cerebral embolism, cerebral ischemia, extrasystoles, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation.

    Digestive SystemFrequent: increased appetite; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, stomach ulcer, stomatitis, thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, salivary gland enlargement, tongue edema.

    Endocrine SystemInfrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus.

    Hemic and Lymphatic SystemInfrequent: anemia, ecchymosis; Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia.

    Metabolic and NutritionalInfrequent: dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased.

    Musculoskeletal SystemInfrequent: arthritis, bone pain, bursitis, leg cramps, tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis.

    Nervous SystemFrequent: amnesia, emotional lability, paresthesia, and sleep disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder1, psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, stupor.

    Respiratory SystemInfrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor.

    Skin and AppendagesInfrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer; Rare: furunculosis, herpes zoster, hirsutism, psoriasis, purpuric rash, seborrhea.

    Special SensesFrequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect.

    Urogenital SystemInfrequent: abortion2, albuminuria, amenorrhea2, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation2, fibrocystic breast2, hematuria, leukorrhea2, menorrhagia2, metrorrhagia2, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage2; Rare: breast engorgement, glycosuria, hypomenorrhea2, kidney pain, oliguria, uterine hemorrhage2, uterine fibroids enlarged2.

    1             Personality disorder is the COSTART term for designating non-aggressive objectionable behavior.

    2             Adjusted for gender.

    6.3       Postmarketing   Experience


    The following adverse reactions have been identified during post approval use of fluoxetine. 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 fibrillation1, 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, 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 reactions, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

    7       DRUG   INTERACTIONS


    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
    • Pimozide: Flumusa (Fluoxetine Hydrochloride) is contraindicated for use with pimozide due to risk of drug interaction or QTc prolongation
    • 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 SARAFEM
    • Drugs   Metabolized   by   CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway 
    • Tricyclic   Antidepressants   (TCAs): Monitor TCA levels during coadministration with SARAFEM or when SARAFEM has been recently discontinued 
    • CNS   Acting   Drugs: Caution should be used when taken in combination with other centrally acting drugs  
    • Benzodiazepines: Diazepam – increased t½ , alprazolam - further psychomotor performance decrement due to increased levels 
    • Antipsyc h otics: Potential for elevation of haloperidol and clozapine levels 
    • Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity 
    • Serotonergic   Drugs: Potential for Serotonin Syndrome 
    • Triptans: There have been rare postmarketing reports of Serotonin Syndrome with use of an SSRI and a triptan ( 5.27.4 )
    • Tryptophan: Concomitant use with tryptophan is not recommended 
    • Drugs   that   Interfere   with   Hemostasis   ( for example ,   NSAIDs,   Aspirin,   Warfarin): May potentiate the risk of bleeding 
    • Drugs   Tightly   Bound   to   Plasma   Proteins: May cause a shift in plasma concentrations  

    7.1       Monoamine   Oxidase   Inhibitors   (MAOI)


    Concomitant use of SARAFEM (fluoxetine) in patients taking MAOIs is contraindicated. 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, fluoxetine, including SARAFEM, 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 Dosage and Administration ( 2.4 and 2.5 ), Contraindications (4.1) , Warnings and Precautions (5.2) , and Clinical Pharmacology (12.3) ].

    7.2       CNS   Acting   Drugs  


    Caution is advised if the concomitant administration of fluoxetine, including SARAFEM, and other CNS acting 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 ].

    7.3       Serotonergic   Drugs


    Based on the mechanism of action of SNRIs and SSRIs, including SARAFEM, and the potential for serotonin syndrome, caution is advised when SARAFEM 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, amphetamines, or St. John’s Wort [see Warnings and Precautions (5.2) ]. The concomitant use of SARAFEM with SNRIs, SSRIs, or tryptophan is not recommended [see Dosage and Administration ( 2.4 and 2.5 ), Contraindications (4.1) , Warnings and Precautions (5.2) , and 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 SARAFEM with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions and Drug Interactions (7.3) ].

    7.5       Tryptophan


    Five patients receiving fluoxetine 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 fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

    7.8       Potential   for   Other   Drugs   to   affect   SARAFEM


    Drugs   Tightly   Bound   to   Plasma   Proteins — Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly bound drugs [see   Clinical Pharmacology  ]

    7.9       Potential   for   SARAFEM   to   affect   Other   Drugs


    Pimozide — Concomitant use of SARAFEM 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 — Concomitant use of SARAFEM in patients taking thioridazine is contraindicated. 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 Cmax 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 fluoxetine, will produce elevated plasma levels of thioridazine.

    Thioridazine administration produces a dose-related prolongation of the QTc 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 (for example, tricyclic antidepressants (TCAs)), antipsychotics (for example, phenothiazines and most atypicals), and antiarrhythmics (for example, 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 (for example, 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) ].

    Benzodiazapines — 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 fluoxetine. 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 (for example, warfarin, 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 fluoxetine.

    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.

    8       USE   IN   SPECIFIC   POPULATIONS

    • Pregnancy: PMDD does not exist during pregnancy. Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus 
    • Nursing   Mothers: Breast feeding is not recommended 
    • Hepatic   Impairment: Lower or less frequent dosing may be appropriate in patients with cirrhosis 

    8.1       Pregnancy  


    Pregnancy Category C — It should be noted that the diagnosis of PMDD does exist during pregnancy. Flumusa 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 = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established.

    Nonteratogenic Effects — Neonates exposed to Flumusa (Fluoxetine Hydrochloride) and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2) ].

    Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest a positive statistical association between SSRI use (including fluoxetine) in pregnancy and PPHN. Other studies do not show a significant statistical association. 

    Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.

    When treating a pregnant woman with fluoxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. The decision can only be made on a case by case basis.

    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 (Fluoxetine Hydrochloride) 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 is excreted in human milk, nursing while on SARAFEM 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 295.0 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


    Safety and effectiveness of SARAFEM in the pediatric population have not been established [see Boxed Warning and Warnings and Precautions (5.1) ]. When considering the use of SARAFEM in a child or adolescent, the potential risks must be balanced 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 fluoxetine. Some of these effects occurred at clinically relevant exposures.

    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) ].

    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/m2) 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/m2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain.

    8.5       Geriatric   Use


    The diagnosis of PMDD is not applicable to postmenopausal women. 

    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 SARAFEM in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].

    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 pre-marketing 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 SARAFEM (for example, 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 fluoxetine, 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 SSRI.

    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).

    11       DESCRIPTION


    SARAFEM (fluoxetine hydrochloride tablets) is a selective serotonin reuptake inhibitor (SSRI) for oral administration. It is designated (±)-N-methyl-3-phenyl-3-[(α, α, α -trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is:

    Dose Analyte Cmax
    (ng/mL)
    Tmax 
    (hour)
    AUC(0-t)
    (ng·h/mL)
    T1/2 a
    (hour)
    SARAFEM 20 mg Fluoxetine 13.2 (22) 8.0 (2.0-10.0) 722.4 (138) 26.5 (15.7-310.0)
    Norfluoxetine 9.7 (37) 48.0 (11.0-144.0) 2114.3 (41) 110.4 (66.8-308.0)
    a)  3 subjects had longer fluoxetine elimination half-life values ranging from 100-300 hours; see Clinical issues relating to metabolism/elimination for more information on “poor metabolizers” 

    Food does not appear to affect the systemic bioavailability of fluoxetine, 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 [see Drug Interactions ( 7.8 and 7.9 )].

    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 fluoxetine. 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.

    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 fluoxetine. 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) ].

    Excretion — The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.

    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 SARAFEM.

    Hepatic Impairment — As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. 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 (2.3) , Use in Specific Populations (8.6) ].

    Renal Impairment — 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.

    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

    14.1       Premenstrual   Dysphoric   Disorder  


    The effectiveness of SARAFEM for the treatment of PMDD was established in 3 placebo-controlled trials (1 intermittent and 2 continuous dosing). In an intermittent dosing trial described below, patients met Diagnostic and Statistical Manual-4th edition (DSM-IV) criteria for PMDD. In the continuous dosing trials described below, patients met Diagnostic and Statistical Manual-3rd edition revised (DSM-IIIR) criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as PMDD in the DSM-IV. Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of Flumusa (Fluoxetine Hydrochloride) in combination with oral contraceptives for the treatment of PMDD is unknown.

    In an intermittent dosing double-blind, parallel group study of 3 months duration, patients (N = 260 randomized) were treated with Flumusa (Fluoxetine Hydrochloride) 10 mg/day, Flumusa (Fluoxetine Hydrochloride) 20 mg/day, or placebo. Flumusa (Fluoxetine Hydrochloride) or placebo was started 14 days prior to the anticipated onset of menstruation and was continued through the first full day of menses. Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms. Flumusa (Fluoxetine Hydrochloride) 20 mg/day was shown to be significantly more effective than placebo as measured by the DRSP total score. Flumusa (Fluoxetine Hydrochloride) 10 mg/day was not shown to be significantly more effective than placebo on this outcome. The average DRSP total score decreased 38% on Flumusa (Fluoxetine Hydrochloride) 20 mg/day, 35% on Flumusa (Fluoxetine Hydrochloride) 10 mg/day, and 30% on placebo.

    In the first continuous dosing double-blind, parallel group study of 6 months duration involving N = 320 patients, fixed doses of Flumusa (Fluoxetine Hydrochloride) 20 and 60 mg/day given daily throughout the menstrual cycle were shown to be significantly more effective than placebo as measured by a Visual Analogue Scale (VAS) total score (including mood and physical symptoms). The average total VAS score decreased 7% on placebo treatment, 36% on 20 mg, and 39% on 60 mg fluoxetine. The difference between the 20 and 60 mg doses was not statistically significant. The following table shows the percentage of patients meeting criteria for either moderate or marked improvement on the VAS total score:

       Improvement N Placebo N Fluoxetine   20   mg N Fluoxetine   60   mg
      Moderate 94 11% 95 37% 85 38%
      Marked 94 4% 95 6% 85 18%

    In a second continuous dosing double-blind, cross-over study, patients (N = 19) were treated with Flumusa (Fluoxetine Hydrochloride) 20 to 60 mg/day (mean dose = 27 mg/day) and placebo daily throughout the menstrual cycle for a period of 3 months each. Flumusa (Fluoxetine Hydrochloride) was significantly more effective than placebo as measured by within cycle follicular to luteal phase changes in the VAS total score (mood, physical, and social impairment symptoms). The average VAS total score (follicular to luteal phase increase) was 3.8 times higher during placebo treatment than what was observed during Flumusa (Fluoxetine Hydrochloride) treatment.

    In another continuous dosing double-blind, parallel group study, patients with LLPDD (N = 42) were treated daily with Flumusa (Fluoxetine Hydrochloride) 20 mg/day, bupropion 300 mg/day, or placebo for 2 months. Neither Flumusa (Fluoxetine Hydrochloride) nor bupropion was shown to be superior to placebo on the primary endpoint, that is, response rate [defined as a rating of 1 (very much improved) or 2 (much improved) on the CGI], possibly due to sample size.

    16       HOW   SUPPLIED/STORAGE   AND   HANDLING

    16.1       How   Supplied


    SARAFEM® is available in 10 mg1, 15 mg1 and 20 mg1 strengths.

    The 10 mg tablet is a cream, round tablet embossed with S10 on one side:

          N DC 0430-0210-14 - Four blister cards of 7 tablets each

    The 15 mg tablet is a white, round tablet embossed with S15 on one side:

          N DC 0430-0215-14 - Four blister cards of 7 tablets each

    The 20 mg tablet is a yellow, round tablet embossed with S20 on one side:

          N DC 0430-0220-14 - Four blister cards of 7 tablets each

    ________________

    1       Equivalent to Flumusa (Fluoxetine Hydrochloride) base.

    16.2       Storage   and   Handling


    Store at 25˚ C (77˚ F); excursions permitted to 15˚ - 30˚ C (59˚ - 86˚ F) [see USP Controlled Room Temperature]

    17       PATIENT   COUNSELING   INFORMATION


    See the FDA-approved Medication Guide .

    17.1       General Information


    Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with SARAFEM 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 SARAFEM 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 SARAFEM.

    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 Boxed Warning and Warnings and Precautions (5.1) ].

    17.3       Serotonin Syndrome


    Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SARAFEM and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan, and St. John’s Wort [see Contraindications (4.1) , Warnings and Precautions (5.2) , and Drug Interactions (7.3) ].

    Patients should be advised of the signs and symptoms associated with serotonin syndrome that may include mental status changes (for example, agitation, hallucinations, delirium, and coma), autonomic instability (for example, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (for example, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (for example, nausea, vomiting, diarrhea). 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 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 SARAFEM.

    17.6       Angle-Closure Glaucoma


    Patients should be advised that taking SARAFEM can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure, if they are susceptible [See Warnings and Precautions (5.8) ].

    17.7       Hyponatremia


    Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including SARAFEM. 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 (5.9) ].

    17.8       Potential for Cognitive and Motor Impairment


    SARAFEM 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 ].

    17.9       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, Prozac, Prozac Weekly, 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 SARAFEM.

    17.10       Discontinuation of Treatment


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

    17.11       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 (Fluoxetine Hydrochloride) 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 breastfeed an infant during therapy. Because Flumusa (Fluoxetine Hydrochloride) is excreted in human milk, nursing while taking SARAFEM is not recommended [see Use in Specific Populations (8.3) ].

    Distributed by:
    Allergan USA, Inc.
    Irvine, CA 92612
    Sarafem® is a registered trademark of Allergan Pharmaceuticals International Limited
    © 2016 Allergan. All rights reserved.

    01/2017

    Medication Guide

    SARAFEM® (SAIR-a-fem)
    (fluoxetine hydrochloride)

     Tablets

    Read the Medication Guide that comes with SARAFEM 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 you want to learn more about.

    SARAFEM is in a class of drugs called selective serotonin reuptake inhibitors (SSRIs), which are often used for the treatment of depression and anxiety disorders. Although SARAFEM is not a treatment for depression, it contains Flumusa (Fluoxetine Hydrochloride) hydrochloride, the same active ingredient in some antidepressants.

    What is the most important information I should know about SARAFEM?

    SARAFEM and other antidepressant medicines may cause serious side effects including:

    1. Suicidal thoughts or actions:

    • SARAFEM 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 SARAFEM 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. SARAFEM may be associated with these serious side effects:

    2. Serotonin Syndrome. 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
    • dizziness
    • flushing
    • tremor
    • seizures

    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. 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

    5. Seizures or convulsions

    6. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment.

    7. Abnormal bleeding: SARAFEM 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 (NSAID’s, like ibuprofen or naproxen), or aspirin.

    8. Visual Problems

    • eye pain
    • changes in vision
    • swelling or redness in or around the eye

    Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

    9 . 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 SARAFEM without first talking to your healthcare provider. Stopping SARAFEM 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 is SARAFEM?

    SARAFEM is a prescription medicine used to treat premenstrual dysphoric disorder (PMDD).

    It is not known if SARAFEM is safe and effective in children.

    Talk with your healthcare provider if you do not think that your condition is getting better with SARAFEM treatment.

    Who should not take SARAFEM?

    Do not take SARAFEM if you:

    • take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
      ○ Do not take an MAOI within 5 weeks of stopping SARAFEM unless directed to do so by your healthcare provider.
      ○ Do not start SARAFEM if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare provider.

    Women who take SARAFEM 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 SARAFEM 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 SARAFEM? Ask if you are not sure.

    Before starting SARAFEM, 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, buspirone, amphetamines, SSRIs, SNRIs, MAOIs or antipsychotics
      ○ Tramadol and fentanyl
      ○ 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 SARAFEM will harm your unborn baby.
    • are breastfeeding or plan to breastfeed. Some SARAFEM may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking SARAFEM.

    Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. SARAFEM 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 SARAFEM with your other medicines. Do not start or stop any medicine while taking SARAFEM without talking to your healthcare provider first.

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

    • Symbyax ®
    • Prozac ®
    • Prozac ® WeeklyTM

    How should I take SARAFEM?

    • Take SARAFEM exactly as prescribed. Your healthcare provider may need to change the dose of SARAFEM until it is the right dose for you.
    • Talk to your healthcare provider if your symptoms do not get better.
    • SARAFEM may be taken with or without food.
    • If you take too much SARAFEM, call your healthcare provider or go to the nearest hospital emergency room right away.

    What should I avoid while taking SARAFEM?

    SARAFEM 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 SARAFEM affects you. Do not drink alcohol while using SARAFEM.

    What are the possible side effects of SARAFEM?

    SARAFEM may cause serious side effects, including:

    • See “What is the most important information I should know about SARAFEM?”
    • Problems with blood sugar control. Women who have diabetes and take SARAFEM may have problems with low blood sugar while taking SARAFEM. High blood sugar can happen when SARAFEM is stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking SARAFEM.
    • Feeling anxious or trouble sleeping

    The most common side effects of SARAFEM include:

    • headache
    • weakness (asthenia)
    • pain
    • accidental injury
    • infection
    • flu symptoms
    • nausea
    • diarrhea
    • trouble sleeping (insomnia)
    • dizziness
    • feeling anxious or nervous
    • thinking differently
    • sexual problems
    • runny or stuffy nose (rhinitis)
    • sore throat (pharyngitis)

    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 SARAFEM. For more information, ask your healthcare provider or pharmacist.

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

    How should I store SARAFEM?

    • Store SARAFEM at room temperature between 68° F and 77° F (20° C to 25° C).

    Keep SARAFEM and all medicines out of the reach of children.

    General information about SARAFEM

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

    This Medication Guide summarizes the most important information about SARAFEM. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about SARAFEM that is written for healthcare professionals.

    For more information about SARAFEM call 1-800-678-1605.

    What are the ingredients in SARAFEM?

    Active ingredient: Flumusa (Fluoxetine Hydrochloride) hydrochloride

    Inactive ingredients: microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, FD&C Yellow No. 6 aluminum lake (10 mg and 20 mg tablets) and D&C Yellow No. 10 aluminum lake (10 mg and 20 mg tablets)

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

    Distributed by:
    Allergan USA, Inc.
    Irvine, CA 92612

    Sarafem® is a registered trademark of Allergan Pharmaceuticals International Limited

    © 2016 Allergan. All rights reserved.

    01/2017

    PRINCIPAL DISPLAY PANEL

    NDC 0430-0210-14
    Sarafem
    10 mg
    Package of 28 tablets – Four blister cards of 7 tablets
    Rx Only

    PRINCIPAL DISPLAY PANELNDC 0430-0210-14Sarafem10 mgPackage of 28 tablets – Four blister cards of 7 tabletsRx Only

    Principal Display Panel
    Place holder product not currently Marketed.

    Principal Display Panel Place holder product not currently Marketed.

    PRINCIPAL DISPLAY PANEL

    NDC 0430-0220-14
    Sarafem
    20 mg
    Package of 28 tablets – Four blister cards of 7 tablets
    Rx Only

    PRINCIPAL DISPLAY PANELNDC 0430-0220-14Sarafem20 mgPackage of 28 tablets – Four blister cards of 7 tabletsRx Only

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    Flumusa pharmaceutical active ingredients containing related brand and generic drugs, medications or other health care products:

    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. The below information contains the active ingredients of Flumusa.


    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. The below information contains the forms, composition, doses of Flumusa.


    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. The below information contains the destination, category of Flumusa.


    Flumusa indications and usages, anatomical therapeutic chemical and diseases classification 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. The below information contains the Indications and usages, anatomical therapeutic chemical and diseases classification codes of Flumusa.


    Flumusa pharmaceutical companies, researchers, developers, manufacturers, distributors and suppliers:

    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. The below information contains the information about Pharmaceutical companies and Researchers involved in the development of Flumusa.


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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.

    Review

    Medicatione.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.

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    Information checked by Dr. Arunabha Ray, MD Pharmacology

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