Prozac

Potential Interactions with Thioridazine (see also Contraindications): In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C_max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared to the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of cytochrome P4502D6 isozyme activity. Thus, this study suggests that drugs which inhibit P4502D6, 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. Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be concomitantly administered, nor within a minimum of 5 weeks after fluoxetine has been discontinued, nor should PROZAC be administered within 2 weeks after thioridazine has been discontinued (see Contraindications).

The concomitant use of fluoxetine and alcohol on cognitive and psychomotor effects in depressed, panic disorder or OCD patients is not known and is not recommended.

Based on the mechanism of action of fluoxetine and the potential for serotonin syndrome, caution is advised when PROZAC is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and the 5HT₁ agonist, sumatriptan. If concomitant treatment with triptan and an SSRI (e.g. fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram) is clinically warranted, appropriate observation of the patient is advised. The possibility of such interactions should also be considered if other 5HT₁ agonists are to be used in combination with SSRIs (see Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.

In an in vivo interaction study involving co-administration of fluoxetine with single doses of terfenadine (a cytochrome P4503A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P4503A4 activity, to be at least 100 times more potent than fluoxetine 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 cytochrome P4503A4 activity is not likely to be of clinical significance.

Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Consideration should be given to monitoring of clinical status when fluoxetine treatment is initiated in these patients.

Because fluoxetine is highly bound to plasma protein, the administration of fluoxetine to a patient taking another drug which is tightly bound to protein (e.g. warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound fluoxetine by other tightly bound drugs.

The half-life of concurrently administered diazepam may be prolonged in some patients.

Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Consideration should be given to monitoring of clinical status. Experience with the use of PROZAC in combination with other CNS-active drugs is limited and caution is advised if such concomitant medication is required.

Altered anti-coagulant effects, including increased bleeding, have been reported when fluoxetine is co-administered with warfarin. Serious bleeding events have been reported including five with outcome of death. However, a causal relationship to the bleeding events cannot be established. Therefore, patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped.

In patients on stable, maintenance doses of phenytoin, plasma phenytoin concentrations increased substantially and symptoms of phenytoin toxicity appeared (nystagmus, diplopia, ataxia and CNS depression) following initiation of concomitant fluoxetine treatment.

Five patients receiving PROZAC in combination with tryptophan experienced adverse reactions, including agitation, restlessness and gastrointestinal distress.

Combined use of PROZAC and MAO inhibitors is contraindicated due to the potential for serious reactions with features resembling serotonin syndrome or neuroleptic malignant syndrome (see Contraindications; Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

PROZAC, like other agents that are metabolized by the P4502D6 system, inhibits the activity of this isoenzyme. Therefore, co-therapy with medications that are predominantly metabolized by the P4502D6 system and that have a relatively narrow therapeutic index (e.g. flecainide, encainide, vinblastine, carbamazepine and tricyclic antidepressants) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently, or has taken it in the previous 5 weeks. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by P4502D6, the need for decreased dose of the original medication should be considered. The aforementioned drugs with a narrow therapeutic index represent the greatest concern.

Other drugs that have demonstrated increased plasma values or magnified effects when co-administered with fluoxetine include: phenytoin, antipsychotics, benzodiazapines, thioridazine (see Contraindications), St. John's Wort and warfarin.

As fluoxetine is highly bound to plasma proteins, co-administration with another drug which is also highly bound (e.g. warfarin, digitoxin) may result in adverse effects due to an increase in plasma levels of either unbound drug.

There are little data available on the concomitant use of fluoxetine and alcohol.

Elevation of blood levels of haloperidol and clozapine and in some cases, clinical manifestations of toxicity have been observed with coadministration of fluoxetine. Consideration should be given to monitoring of clinical status.

Absorption of fluoxetine is not affected by food.

Interactions with laboratory tests have not been established.

Approximately 3 to 10% of the normal population has a genetic defect that leads to reduced levels of activity of the cytochrome P450 isoenzyme P4502D6. Such individuals have been referred to as “poor metabolizers” of drugs such as debrisoquine, dextrometorphan, sparteine, tricyclic antidepressants (e.g. nortryptiline, amitriptyline, imipramine, and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine) and Type 1C antiarrhythmics (e.g. propafenone and flecainide).

Conversely, approximately 90 to 97% of the normal population do not have this genetic defect, and are known as “extensive metabolizers”. PROZAC, like other agents that are metabolized by the P4502D6 system, inhibits the activity of this isoenzyme, and thus may make normal “extensive” metabolizers resemble “poor metabolizers”. Therapy with medications that are predominantly metabolized by the P4502D6 system and that have a relatively narrow therapeutic index (e.g. flecainide, encainida, vinblastine, carbamazepine and tricyclic antidepressants) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently, or has taken it in the previous 5 weeks.

If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by P4502D6 the need for decreased dose of the original medication should be considered. The aforementioned drugs with a narrow therapeutic index represent the greatest concern.

In common with other SSRI's, pharmacodynamic interactions between fluoxetine and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.

Interactions with PROZAC and herbal remedy St. John's Wort may occur (see Drug-Drug Interactions).

Interaction with lifestyle interactions have not been established.

In two studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2 to 10-fold when fluoxetine has been administered in combination. This influence may persist for three weeks or longer after fluoxetine is discontinued. Thus, the dose of tricyclic antidepressant (TCA) may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued. See Warnings and Precautions; and Action and Clinical Pharmacology, Accumulation and Slow Elimination.

When dosing is stopped, active drug substances will persist in the body for weeks. This should be borne in mind when starting or stopping treatment. Dosage tapering is unnecessary in most patients.

Despite its long-half life, symptoms associated with the discontinuation of PROZAC have been reported in clinical trials and post-marketing. Patients should be monitored for these and other symptoms when discontinuing treatment, regardless of the indication for which PROZAC is being prescribed. PROZAC (fluoxetine) has been only rarely associated with such symptoms. Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy, which makes dose tapering unnecessary in most patients (see Warnings and Precautions and Adverse Reactions).

A lower or less frequent dosage should be used in patients with renal and/or hepatic impairment and in those on multiple medications.

The recommended dosage is 60 mg per day, although studies show that lower doses may also be efficacious. Electrolyte levels should be assessed prior to initiation of treatment.

PROZAC (fluoxetine) is not indicated for use in children under 18 year of age (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

Fluoxetine was evaluated in depressed elderly patients only at a dosage of 20 mg/day. A lower or less frequent dosage may be effective and should be considered in elderly patients with concurrent disease or on multiple medications.

Dosage of a TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Drug Interactions, Tricyclic Antidepressants).

The usual initial dosage is 20 mg administered once daily in the morning. A gradual dose increase should be considered only after a trial period of several weeks if the expected clinical improvement does not occur. Dosage should not exceed a maximum of 80 mg per day since clinical experience with doses above 80 mg per day is very limited.

For any indication, the total fluoxetine dosage should not exceed a maximum of 80 mg per day since clinical experience with doses above 80 mg per day is very limited.

During maintenance therapy, the dosage should be kept at the lowest effective level.

A dose range of 20 mg/day to 60 mg/day is recommended for the treatment of obsessive-compulsive disorder.

Since it may take up to four or five weeks to reach steady-state plasma levels of PROZAC (fluoxetine), sufficient time should be allowed to elapse before dosage is gradually increased. Higher dosages are usually associated with an increased incidence of adverse reactions.

PROZAC (fluoxetine) is not indicated for use in children under 18 year of age (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

The efficacy of PROZAC in maintaining an antidepressant response for up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) was demonstrated in a placebo-controlled trial. The usefulness of the drug in patients receiving PROZAC for extended periods should be reevaluated periodically.

At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with PROZAC. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping PROZAC before starting MAOI (see Contraindications).

Post-marketing reports indicate that some neonates exposed to PROZAC, SSRIs or other newer anti-depressants, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see Warnings and Precautions). When treating pregnant women with PROZAC during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering PROZAC in the third trimester.

PROZAC is not indicated for use in patients below the age of 18 years (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

Decreased weight gain and a lesser gain in height have been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine (n=88) were recorded as gaining an average of 1.1 cm less in height than subjects treated with placebo (n=75). However, the study was not designed for a rigorous assessment of growth (e.g., heights were recorded to the nearest rounded inch), and thus a definite interpretation of this finding was compromised. This is exemplified by the reported outcome of a loss in height for 17 of the patients. Notwithstanding these limitations, an attenuation of height gain with acute fluoxetine treatment cannot be excluded. Fluoxetine treatment was also associated with a decrease in serum alkaline phosphatase levels in this study. Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving fluoxetine.

Voluntary reports of adverse events temporally associated with PROZAC that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice, confusion, 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 fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of preexisting movement disorders, neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a range of signs and symptoms that can rarely, in most severe cases, resemble neuroleptic malignant syndrome), Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia (including torsades de pointes-type arrhythmias) and violent behaviours.

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

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Multiple doses of PROZAC had been administered to 10 782 patients with various diagnoses in US clinical trials as of May 8, 1995. Adverse events 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 events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories.

In clinical trials, the most commonly observed adverse events associated with the use of PROZAC (fluoxetine) and not seen at an equivalent incidence among placebo treated patients were: central nervous system complaints, including headache, nervousness, insomnia, drowsiness, fatigue or asthenia, anxiety, tremor, and dizziness or lightheadedness; gastrointestinal complaints, including nausea, diarrhea, dry mouth and anorexia; and excessive sweating.

Symptoms associated with discontinuation of PROZAC have been reported in clinical trials and post-marketing (e.g. headache, insomnia, paresthesias, nervousness, anxiety, nausea, sweating, numbness, dizziness, jitteriness, asthenia, or other symptoms which may be of clinical significance). The majority of these are mild and self-limiting. PROZAC (fluoxetine) has been only rarely associated with such symptoms. Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy, which makes dose tapering unnecessary in most patients. See Warnings and Precautions, General; and Dosage and Administration.

Fifteen percent of approximately 4000 patients who received PROZAC in North American clinical trials discontinued treatment due to an adverse event. The more common events causing discontinuation from depression trials in adults and elderly, included: psychiatric, primarily nervousness, anxiety, and insomnia; digestive, primarily nausea; nervous system, primarily dizziness, asthenia, and headaches; skin, primarily rash and pruritus.

In obsessive compulsive disorder studies, 12.1% of fluoxetine treated patients discontinued treatment early because of adverse events. Anxiety and rash, at incidences of less than 2%, were the most frequently reported events. In bulimia nervosa studies, 10.2% of fluoxetine treated patients discontinued treatment early because of adverse events. Insomnia, anxiety and rash, at incidences of less than 2%, were the most frequently reported events.

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

Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash. Rare: furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea.

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

Frequent: chills. Infrequent: chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide attempt. Rare: abdominal syndrome acute, hypothermia, intentional injury, neuroleptic malignant syndrome{*Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome.} (characterized by the clustering of clinical features of changes in mental state and neuromuscular activity, in combination with autonomic nervous system dysfunction), photosensitivity reaction.

Following is a list of all treatment-emergent adverse events reported at anytime by individuals taking fluoxetine in US clinical trials (10 782 patients) except: (1) those listed in the body or footnotes of Table 1 or Table 2 above or elsewhere in labelling; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to PROZAC use was considered remote; and (4) events occurring in only 1 patient treated with PROZAC and which did not have a substantial probability of being acutely life-threatening.

Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 but at least 1/1000 patients; rare events are those occurring in less than 1/1000 patients.

Frequent: hemorrhage, hypertension. Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache. Rare: atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation.

Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.

Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in depression, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia.

There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Infrequent: hypothyroidism. Rare: diabetic acidosis, diabetes mellitus.

Suicidal thoughts and acts are far more common among depressed patients than in the general population. It is estimated that suicide is 22 to 36 times more prevalent in depressed persons than in the general population. A comprehensive meta-analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder compared fluoxetine (n=1765) with a tricyclic antidepressant (n=731) or placebo (n=569), or both. The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants.

In countries where the drug has already been marketed, the following potentially serious adverse reactions have been reported; interactions with MAO inhibitors and possibly other drugs, allergic reactions, cardiovascular reactions, syndrome of inappropriate ADH secretion, and grand mal seizure. Death and life-threatening events have been associated with some of these reactions, although causal relationship to PROZAC has not necessarily been established.

Post-marketing experience also confirms the profile of adverse reactions commonly reported during clinical trials with PROZAC including allergic skin reactions.

Frequent: agitation, amnesia, confusion, emotional lability, sleep disorder. Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder{†Personality disorder is the COSTART term for designating non-aggressive objectionable behavior.}, psychosis, vertigo. Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor.

Frequent: urinary frequency. Infrequent: abortion{‡Adjusted for gender.}, albuminuria, amenorrhea‡, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation‡, fibrocystic breast‡, hematuria, leukorrhea‡, menorrhagia‡, metrorrhagia‡, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage‡. Rare: breast engorgement, glycosuria, hypomenorrhea‡, kidney pain, oliguria, priapism‡, uterine hemorrhage‡, uterine fibroids enlarged‡.

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

Frequent: weight gain. Infrequent: 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, ALT increased.

Infrequent: anemia, ecchymosis. Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia.

PROZAC is not indicated for use in patients below the age of 18 years. See Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm; see also Adverse Reactions, Potential for Effects on Growth in Pediatric Patients.

Evidence from clinical studies and experience suggests that use in the geriatric population may be associated with differences in safety or effectiveness, and a brief discussion can be found in the appropriate sections (Warnings and Precautions, Special Populations, Geriatrics (≥60 years of age); Dosage and Administration).

PROZAC has been shown to significantly decrease binge-eating and purging activity when compared with placebo treatment.

The effectiveness of PROZAC in long-term use in bulimia nervosa (i.e. for more than 16 weeks) and in obsessive-compulsive disorder (i.e. for more than 13 weeks) has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use PROZAC in these indications for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

PROZAC (fluoxetine) is indicated for the symptomatic relief of Major Depressive Disorder (MDD).

PROZAC is indicated for the symptomatic treatment of obsessive-compulsive disorder (OCD).

The obsessions or compulsions must be experienced as intrusive, markedly distressing, time consuming, or interfering significantly with the person's social or occupational functioning.

The efficacy of PROZAC in hospitalized patients has not been adequately studied.

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 hyper-irritability and convulsions in several animal species.

Among six dogs purposely overdosed with oral fluoxetine, five 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.

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

Among 633 adult patients who overdosed on fluoxetine 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 fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine 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 fluoxetine 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 fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all six overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was non-lethal.

Other important adverse events reported with fluoxetine overdose (single and 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 events, pyrexia stupor, and syncope.

There are no specific antidotes for PROZAC.

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.

Establish and maintain an airway; ensure adequate oxygenation and ventilation.

Cardiac and vital signs monitoring is recommended, along with general symptomatic and supportive measures.

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 considered in treating overdose.

Due to the large volume of distribution of PROZAC, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.

A specific caution involves patients who are taking or have recently taken fluoxetine 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.

Fluoxetine-induced seizures which fail to remit spontaneously may respond to diazepam. (See Product Monograph for diazepam.)

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control centre on the treatment of any overdosage.

Cases of overdose of fluoxetine alone usually have a mild course. Symptoms of overdose included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmias to cardiac arrest, pulmonary dysfunction, and signs of altered CNS status ranging from excitation to coma. Fatalities attributed to overdose of fluoxetine alone have been reported. (Please refer to Human Experience and Animal Experience sections below).

Each green and yellow capsule, printed with Dista 3105 and PROZAC 20 mg, contains: fluoxetine HCl equivalent to fluoxetine 20 mg (64.7 µmoles). Nonmedicinal ingredients: silicone and starch; capsule shell: benzyl alcohol, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium, FD&C Blue No. 1, gelatin, iron oxide yellow, methylparaben, propylparaben, sodium lauryl sulfate, sodium propionate and titanium dioxide. Amber bottles of 100.

Each green capsule, printed with Dista 3104 and PROZAC 10 mg, contains: fluoxetine HCl equivalent to fluoxetine 10 mg (32.3 µmoles). Nonmedicinal ingredients: silicone and starch; capsule shell: benzyl alcohol, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium, FD&C Blue No. 1, gelatin, iron oxide yellow, methylparaben, propylparaben, sodium lauryl sulfate, sodium propionate and titanium dioxide. Amber bottles of 100.

Recent analyses of placebo-controlled clinical trial safety databases from selective serotonin reuptake inhibitors (SSRIs) and other newer anti-depressants suggests that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.

Clinical experience with PROZAC in patients with concomitant systemic illness is limited and it should be used cautiously in such patients, especially those with diseases or conditions that could affect metabolism or hemodynamic responses.

On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment with SSRIs, including PROZAC, particularly when given in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with PROZAC should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. PROZAC should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John's Wort) due to the risk of serotonergic syndrome (see Contraindications and Drug Interactions).

There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking fluoxetine. While there have been reports of abnormal bleeding in several patients taking fluoxetine, it is unclear whether fluoxetine had a causative role.

Safe use of fluoxetine during pregnancy has not been established. Therefore PROZAC should not be administered to women of childbearing potential unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the fetus or the child.

Post-marketing reports indicate that some neonates exposed to PROZAC, other SSRIs (selective serotonin reuptake inhibitors), or newer anti-depressants 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 other newer anti-depressants or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Contraindications, Monoamine Oxidase Inhibitors). When treating a pregnant woman with PROZAC during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Dosage and Administration).

There are no clinical studies to support the safety and efficacy of combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

Post-marketing reports indicate that some neonates exposed to PROZAC, other SSRIs (selective serotonin reuptake inhibitors), or newer anti-depressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. When treating a pregnant woman with PROZAC during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Warnings and Precautions, Special Populations, Pregnant Women; and Dosage and Administration).

In patients with diabetes, fluoxetine 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 fluoxetine is instituted or discontinued.

Self-induced vomiting often leads to hypokalemia which may lower seizure threshold and/or may lead to cardiac conduction abnormalities. Electrolyte levels of bulimic patients should be assessed prior to initiation of treatment.

PROZAC is not indicated for use in patients below the age of 18 years. See Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm. See also Adverse Reactions, Potential for Effects on Growth in Pediatric Patients.

Because of the long elimination half-lives of fluoxetine and its major active metabolite norfluoxetine, 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 (see Action and Clinical Pharmacology; and Dosage and Administration). Even when dosing is stopped, active drug substance will persist in the body for weeks due to the long elimination half-lives of fluoxetine and norfluoxetine. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following discontinuation of PROZAC.

During premarketing testing, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among these cases, 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 these allergic reactions include rash, fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely.

In premarketing clinical trials two 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 severe desquamation that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic manifestations suggestive of serum sickness.

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

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

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

Whether these systemic events 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 events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, PROZAC should be discontinued. Particular caution should be exercised in patients with a history of allergic reactions.

The following additional Precautions are listed alphabetically.

When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation (e.g. headache, insomnia, paresthesias, nervousness, anxiety, nausea, sweating, numbness, dizziness, jitteriness, asthenia or other symptoms which may be of clinical significance).

PROZAC (fluoxetine) has been only rarely associated with such symptoms. Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy, which makes dose tapering unnecessary in most patients (see Warnings and Precautions, General; Adverse Reactions; and Dosage and Administration).

Since clearances of fluoxetine and norfluoxetine may be decreased in patients with impaired liver function including cirrhosis, a lower or less frequent dose should be used in such patients. See Action and Clinical Pharmacology.

Significant weight loss, especially in underweight depressed patients and the elderly, may be an undesirable result of treatment with PROZAC. PROZAC should be given with caution to patients suffering from anorexia nervosa and only if the expected benefits (e.g. co-morbid depression) markedly outweigh the potential weight reducing effect of the drug.

During premarketing clinical trials in a patient population comprised primarily of unipolar depressed patients, hypomania or mania occurred in approximately 1% of fluoxetine treated patients. The incidence in a general patient population which might also include bipolar depressives is unknown. The likelihood of hypomanic or manic episodes may be increased at the higher dosage levels. Such reactions require a reduction in dosage or discontinuation of the drug.

A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should only be made after patients have been adequately assessed to determine if they are at risk for bipolar disorder.

Patients currently taking SSRIs or newer anti-depressants should not be discontinued abruptly, due to risk of discontinuation symptoms. PROZAC has only rarely been associated with such symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer anti-depressant drug, a gradual reduction in the dose rather than an abrupt cessation, except for fluoxetine, is recommended. Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy which makes dose tapering unnecessary in most patients taking this drug (see Warnings and Precautions, Dependence; Adverse Reactions, Adverse Events Subsequent to Discontinuation; and Dosage and Administration, Discontinuation of Treatment).

Patients should be cautioned against driving an automobile or performing hazardous tasks until they are reasonably certain that treatment with PROZAC does not affect them adversely.

Since fluoxetine is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. However, until an adequate number of patients with severe renal impairment have been evaluated in the course of chronic treatment, fluoxetine should be used with caution in such patients.

Evaluation of patients over the age of 60 who received PROZAC 20 mg daily revealed no unusual pattern of adverse events relative to the clinical experience in younger patients. These data are however insufficient to rule out possible age-related differences during chronic use, particularly in elderly patients who have concomitant systemic illnesses or who are receiving concomitant drugs. See Indications and Clinical Use, and Dosage and Administration.

There are clinical trial and post-marketing reports with SSRIs and other newer anti-depressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

Several cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when PROZAC was discontinued. Although these cases were complex with varying possible etiologies, some were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted.

In two 6-week controlled studies in patients ≥60 years of age, 10 of 323 fluoxetine patients and 6 of 327 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration of sodium in a fluoxetine treated patient was 129 mmol/L. The observed decreases were not clinically significant.

PROZAC has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of PROZAC.

PROZAC should be used with caution in patients with a history of convulsive disorders. The incidence of seizures associated with fluoxetine during clinical trials did not appear to differ from that reported with other marketed antidepressants; however, patients with a history of convulsive disorders were excluded from these trials.

Concurrent administration with electroshock therapy should be avoided because of the absence of experience in this area. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. As with other drugs with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviors have been reported during fluoxetine therapy or early after treatment discontinuation. Close supervision of high-risk patients should accompany drug therapy and consideration should be given to the possible need for hospitalization. Physicians should encourage patients of all ages to report any new or worsened distressing thoughts or feelings occurring at any time. In order to minimize the opportunity for overdosage, prescriptions for fluoxetine should be written for the smallest quantity of drug consistent with good patient management.

Because of the well established comorbidity between depression and other psychiatric disorders, the same precautions observed when treating patients with depression should be observed when treating patients with other psychiatric disorders (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

PROZAC and its metabolites are excreted in breast milk, and have been observed to reach high levels in the plasma of nursing infants. Women who are taking PROZAC should not breast feed unless, in the opinion of the treating physician, breast feeding is necessary, in which case the infant should be closely monitored.

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, a 6-week infant, nursed by a mother on PROZAC, developed crying, decreased sleep, vomiting and watery stools. The breast milk showed concentrations of 69 ng/mL for fluoxetine and 90 ng/mL for norfluoxetine. In the infant's plasma, the concentrations of fluoxetine and norfluoxetine on the second day of feeding were 340 and 208 ng/mL, respectively.

PROZAC 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 premarketing clinical studies. Retrospective evaluation of EKGs in some of these studies showed no conduction abnormalities that resulted in heart block. The mean heart rate was reduced by approximately 3 beats/minute.

In patients with cirrhosis, the elimination half-life of fluoxetine was prolonged, with a mean of 7.6 days compared to a range of 2 to 3 days seen in healthy subjects; norfluoxetine half-life was also prolonged, with a mean of 12 days compared to a range of 7 to 9 days in healthy subjects. Fluoxetine should therefore be used with caution in patients with liver disease (see Warnings and Precautions, Hepatic Impairment; and Dosage and Administration).

The effects of age upon the metabolism of fluoxetine have been investigated in a subset of 260 elderly, but otherwise healthy, depressed patients (mean age: 67.4 yr, range 60 to 85 yr) who received 20 mg PROZAC for 6 weeks. Mean plasma concentrations were found to be 89.5±53.6 ng/mL for fluoxetine and 119±51.3 ng/mL for norfluoxetine. However, the effects of concomitant illness and/or concomitant drugs have not been evaluated.

The metabolism of fluoxetine, like that of a number of other compounds, including tricyclic antidepressants and some selective serotonin reuptake inhibitors (SSRIs), involves the P4502D6 system. Concomitant therapy with fluoxetine and the aforementioned drugs may lead to clinically significant drug interactions (see Drug Interactions).

Fluoxetine is well absorbed after oral administration. In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The capsule and oral solution dosage forms of PROZAC are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption inconsequentially. Thus, PROZAC may be administered with or without food.

Fluoxetine is extensively metabolized in the liver to norfluoxetine, and other unidentified metabolites. The pharmacological activity of norfluoxetine, which is formed by demethylation of fluoxetine appears to be similar to that of the parent drug. Norfluoxetine contributes to the long duration of action of PROZAC. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. The elimination half-life of fluoxetine is 4 to 6 days and that of its active metabolite is 4 to 16 days.

After 30 days of dosing at 20 mg/day, mean plasma concentrations of fluoxetine 79.1±33.4 ng/mL and of norfluoxetine 129±42.0 ng/mL have been observed. Plasma concentrations of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) were higher than those predicted by single-dose studies. Norfluoxetine appears to have linear pharmacokinetics. Its mean terminal half-lives after a single dose and multiple doses were 8.6 days and 9.3 days, respectively.

Steady state plasma levels are attained after 4 to 5 weeks of continuous drug administration. Patients receiving fluoxetine at doses of 40 to 80 mg/day over periods as long as 3 years exhibited, on average, plasma concentrations similar to those seen among patients treated for 4 to 5 weeks at the same dose.

In single dose studies, the pharmacokinetics of fluoxetine and norfluoxetine were similar among subjects with all levels of impaired renal function including anephric patients on chronic hemodialysis. However, with chronic administration, additional accumulation of fluoxetine or its metabolites (possibly including some not yet identified) may occur in patients with severely impaired renal function, and the use of a lower or less frequent dose is advised (see Warnings and Precautions, Renal; and Dosage and Administration).

The relatively slow elimination of fluoxetine and its active metabolite, norfluoxetine, results in significant accumulation of these active moieties in chronic use. Therefore, it may take up to 1 to 2 months for the active drug substance(s) to disappear from the body. This persistence of active moieties is important to keep in mind when PROZAC is discontinued, or when drugs that are predicted to interact with PROZAC are to be administered soon after its discontinuation (see Warnings and Precautions, General, Implications of the Long Elimination Half-Life of Fluoxetine; and Drug Interactions).

Approximately 94% of fluoxetine is protein bound. The interaction between fluoxetine and other highly protein bound drugs has not been fully evaluated, but may be important (see Drug Interactions).

The antidepressant, antiobsessional, and antibulimic actions of PROZAC (fluoxetine) are presumed to be linked to its ability to selectively inhibit the neuronal reuptake of serotonin. At clinically relevant doses fluoxetine blocks the uptake of serotonin into human platelets. Antagonism of muscarinic, histaminergic and α₁- adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular effects of classical tricyclic antidepressant drugs. In vitro receptor binding studies have demonstrated that fluoxetine binds to these and other membrane receptors [opiate, serotonergic (5-HT₁, 5-HT₂), adrenergic (α₁,α₂,β) and dopaminergic] much less potently than do the tricyclic drugs.

PROZAC (fluoxetine) is contraindicated in patients with known hypersensitivity to the drug or the excipients of the product. For a complete listing, see Dosage Forms, Composition and Packaging.

Thioridazine should not be administered concomitantly with PROZAC or within a minimum of 5 weeks after PROZAC has been discontinued, nor should PROZAC be administered within 2 weeks after thioridazine has been discontinued.

Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This effect appears to be dose-related.

An in vivo study suggests that drugs which inhibit P4502D₆, including certain SSRI's such as paroxetine, fluoxetine and fluvoxamine, will elevate plasma levels of thioridazine. Therefore, PROZAC should not be used in combination with thioridazine. See Drug Interactions.

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 PROZAC, or other serotonin reuptake inhibitors (SSRIs), in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued PROZAC and then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome (e.g., serotonin syndrome). Therefore, PROZAC should not be used in combination with an MAOI, including either within a minimum of 14 days of discontinuing therapy with an MAOI, or a minimum of 5 weeks of discontinuing therapy with PROZAC. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping PROZAC before starting an MAOI. Limited reports suggest that intravenously administered dantrolene (Dantrium) or orally administered cyproheptadine (Periactin) may benefit patients experiencing such reactions. See Drug Interactions.