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.
Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water.
Each SARAFEM tablet contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 15 mg (48.5 μmol) or 20 mg (64.7 μmol) of fluoxetine. Each tablet also contains microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, FD&C Yellow No. 6 aluminumlake (10 mg and 20 mg tablets) and D&C Yellow No. 10 aluminum lake (10 mg and 20 mg tablets).
Mechanism of Action
Although the exact mechanism of SARAFEM is unknown, it is presumed to be linked to its inhibition ofCNS neuronal uptake of serotonin.
INDICATIONS AND USAGE
Premenstrual Dysphoric Disorder (PMDD): SARAFEM is indicated for the treatment of premenstrual dysphoric disorder (PMDD)
DOSAGE AND ADMINISTRATION
The recommended dose of SARAFEM for the treatment of PMDD is 20 mg/day given continuously (every day of the menstrual cycle) 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.
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
Dosing in Specific Populations
Treatment of Pregnant Women: PMDD does not exist in pregnancy. However, if there is a need to treatpregnant 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.
Hepatic Impairment: A lower or less frequent dosage should be used in patients with hepatic impairment
Concomitant Illness: Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments
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 psychiatricdisorders 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
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 bluebecause 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.
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.
The use of SARAFEM is contraindicated with the following:
WARNINGS AND PRECAUTIONS
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.
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 (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) 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.
Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania: A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for Bipolar Disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such aconversion 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.
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.
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.
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 (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when fluoxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volumedepleted may be at greater risk
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.
Discontinuation of Treatment: During marketing of SARAFEM, SNRIs, and SSRIs, there have been spontaneous reports of adversereactions 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.
Sexual Dysfunction: Use of SSRIs, including SARAFEM, may cause symptoms of sexual dysfunction. In female patients, SSRI /SNRI use may result in decreased libido and delayed or absent orgasm.
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 fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI.
CNS Acting Drugs: Caution is advised if the concomitant administration of fluoxetine, including SARAFEM, and other CNSacting 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.
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. The concomitant use of SARAFEM with SNRIs, SSRIs, or tryptophan is not recommended.
Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. Ifconcomitant treatment of SARAFEM with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
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.
Drugs that Interfere with Hemostasis (for example, NSAIDS, Aspirin, Warfarin): 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 fluoxetine is initiated or discontinued
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 fluoxetine has not been conducted, the potentialfor drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and fluoxetine
Thioridazine:Concomitant use of SARAFEM in patients taking thioridazine is contraindicated. Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued
USE IN SPECIFIC POPULATIONS
Pregnancy Category C: It should be noted that the diagnosis of PMDD does exist during pregnancy. Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The effect of fluoxetine on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on thenewborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Because fluoxetine is excreted in human milk, nursing while on SARAFEM is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL ofnorfluoxetine on the second day of feeding.
Geriatric Use: The diagnosis of PMDD is not applicable to postmenopausal women.
The following have been reported with fluoxetine tablet overdosage:
- Seizures, which may be delayed, and altered mental status including coma.
- Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, torsade de pointes, and cardiac arrest. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.
- Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk).
Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a fluoxetine overdose.
Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for overdosagemanagement recommendations.