Fluoxetine/olanzapine Disease Interactions

Older patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death; although the causes were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. A causal relationship with antipsychotic use has not been established. In controlled trials in older patients with dementia-related psychosis, patients randomized to risperidone, aripiprazole, and olanzapine had higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, compared to patients treated with placebo. These agents are not approved for the treatment of patients with dementia-related psychosis.

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The use of neuroleptic agents is contraindicated in patients with acute alcohol intoxication exhibiting depressed vital signs. The central nervous system depressant effects of neuroleptic agents may be additive with those of alcohol. Severe respiratory depression and respiratory arrest may occur. Therapy with neuroleptic agents should be administered cautiously in patients who might be prone to acute alcohol intake.

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The use of neuroleptic agents is contraindicated in comatose patients and patients with severe central nervous system depression. Neuroleptic agents may potentiate the CNS and respiratory depression in these patients.

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The central dopaminergic blocking effects of neuroleptic agents may precipitate or aggravate a potentially fatal symptom complex known as neuroleptic malignant syndrome (NMS). NMS is observed most frequently when high-potency agents like haloperidol are administered intramuscularly, but may occur with any neuroleptic agent given for any length of time. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac arrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria, and acute renal failure. Neuroleptic agents should not be given to patients with active NMS and should be immediately discontinued if currently being administered in such patients. In patients with a history of NMS, introduction or reintroduction of neuroleptic agents should be carefully considered, since NMS may recur.

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Adult and pediatric patients with depression and other psychiatric disorders may experience worsening of their symptoms and may have the emergence of suicidal thoughts and behavior. Patients should be monitored appropriately and observed closely for worsening of their symptoms, suicidality or changes in their behavior, especially during the first few months of treatment, and at times of dose changes. Families and caregivers should be advised of the need for close observation and communication with the treating physician. Discontinuing the medication should be considered if symptoms are persistently worse, or abrupt in onset. It may be prudent to refrain from dispensing large quantities of medication to these patients.

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Esophageal dysmotility and aspiration have been associated with the use of antipsychotic drugs. These drugs should be administered cautiously in patients at risk for aspiration pneumonia.

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Antipsychotic and neuroleptic drugs can lower the seizure threshold and trigger seizures in a dose-dependent manner. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Therapy with these drugs should be administered cautiously in patients with a history of seizures or other predisposing factors, such as head trauma, CNS abnormalities, and alcoholism.

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Cases of leukopenia, neutropenia, and agranulocytosis have been reported with the use of atypical antipsychotic agents. Patients with preexisting low white blood cell count may be at increased risk. Therapy with these agents should be administered cautiously in patients with a history of, or predisposition to, decreased white blood cell or neutrophil counts. Clinical monitoring of hematopoietic function is recommended. At the first sign of a clinically significant decline in white blood cells, discontinuation of atypical antipsychotic therapy should be considered in the absence of other causative factors, and the patient closely monitored for fever or other signs and symptoms of infection.

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Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported with the use of atypical antipsychotic agents. Patients with diabetes should be monitored for worsening control of blood glucose when treated with these agents. It is recommended that patients with risk factors for diabetes mellitus starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment, and periodically thereafter. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when treatment with these agents was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the atypical antipsychotic drug.

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The use of atypical antipsychotic agents has been associated with orthostatic hypotension and syncope. Therapy with atypical antipsychotics should be administered cautiously in patients with hypotension or conditions that could be exacerbated by hypotension, such as a history of myocardial infarction, angina, or ischemic stroke. Patients with dehydration (e.g., due to severe diarrhea or vomiting) may be predisposed to hypotension and should also be managed carefully during therapy with atypical antipsychotics. Blood pressure should be monitored at regular intervals, particularly during dosage escalation or whenever dosage has been altered, and patients should be advised not to rise abruptly from a sitting or recumbent position.

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Atypical antipsychotic drugs have been associated with undesirable alterations in lipid levels. While all agents in the class have been shown to produce some changes, each drug has its own specific risk profile. Before or soon after initiation of antipsychotic medications, a fasting lipid profile should be obtained at baseline and monitored periodically during treatment.

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Weight gain has been observed with atypical antipsychotic use. While all agents in the class have been shown to produce some changes, each drug has its own specific risk profile. When treating pediatric patients with atypical antipsychotic agents, weight gain should be monitored and assessed against that expected for normal growth. Monitor weight at baseline and frequently thereafter.

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Adult and pediatric patients with depression and other psychiatric disorders may experience worsening of their symptoms and may have the emergence of suicidal thoughts and behavior. Patients should be monitored appropriately and observed closely for worsening of their symptoms, suicidality or changes in their behavior, especially during the first few months of treatment, and at times of dose changes. Discontinuing the medication should be considered if symptoms are persistently worse, or abrupt in onset.

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Fluoxetine may alter blood glucose control in patients with diabetes. Hypoglycemia may occur during therapy with fluoxetine, and hyperglycemia may occur following discontinuation of the drug. Dosage adjustments in insulin and/or oral hypoglycemic medications may be necessary in patients with diabetes whenever fluoxetine therapy is initiated or discontinued.

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Most neuroleptic agents have anticholinergic activity, to which elderly patients are particularly sensitive. Clozapine and low- potency agents such as chlorpromazine and thioridazine tend to exhibit the greatest degree of anticholinergic effects in the class, while haloperidol as well as the newer, atypical agents like quetiapine, risperidone and ziprasidone have generally been associated with very low frequencies of anticholinergic adverse effects. Therapy with neuroleptic agents should be administered cautiously in patients with preexisting conditions that are likely to be exacerbated by anticholinergic activity, such as urinary retention or obstruction; angle-closure glaucoma, untreated intraocular hypertension, or uncontrolled primary open-angle glaucoma; and gastrointestinal obstructive disorders.

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The chronic use of neuroleptic agents can cause persistent elevations in prolactin levels due to antagonism of dopamine D2 receptors. Based on in vitro data, approximately one-third of human breast cancers are thought to be prolactin-dependent. The clinical significance of this observation with respect to long-term neuroleptic therapy is unknown. Chronic administration of neuroleptic drugs has been associated with mammary tumorigenesis in rodent studies but not in human clinical or epidemiologic studies. Until further data are available, therapy with neuroleptic agents should be administered cautiously in patients with a previously detected breast cancer. Caution is also advised in patients with preexisting hyperprolactinemia. Hyperprolactinemia may suppress hypothalamic gonadotrophin releasing hormone (GnRH), resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds; however, the clinical significance of elevated serum prolactin levels is unknown for most patients. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients.

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Most neuroleptic agents are extensively metabolized by the liver. The plasma concentrations of these agents may be increased and the half-lives prolonged in patients with impaired hepatic function. Therapy with neuroleptic agents should be administered cautiously in patients with significant liver disease. Lower initial dosages and slower titration may be appropriate.

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The use of neuroleptic agents is associated with pseudo-parkinsonian symptoms such as akinesia, bradykinesia, tremors, pill-rolling motion, cogwheel rigidity, and postural abnormalities including stooped posture and shuffling gait. The onset is usually 1 to 2 weeks following initiation of therapy or an increase in dosage. Older neuroleptic agents such as haloperidol are more likely to induce these effects, and their use may be contraindicated in patients with Parkinson's disease or parkinsonian symptoms.

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Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs; the syndrome consists of potentially irreversible, involuntary, dyskinetic movements. The risk appears highest in older patients (particularly older women) but it is not possible to predict which patients are likely to develop TD; whether antipsychotic drugs differ in their potential to cause TD is unknown. The risk of TD and the likelihood that it will become irreversible increase with the duration of therapy and the total cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low dosages; it may also occur after discontinuation of therapy. TD may remit (partially or completely) upon discontinuation of antipsychotic therapy, although antipsychotic therapy itself may suppress (or partially suppress) signs/symptoms of TD, possibly masking the underlying process; the effect of symptomatic suppression on the long-term course of TD is unknown. In patients with preexisting drug-induced TD, initiating or increasing the dosage of antipsychotic therapy may temporarily mask the symptoms of TD but could eventually worsen the condition. In patients requiring chronic therapy, the lowest dose and shortest duration of therapy producing a satisfactory clinical response are recommended; the need for continued therapy should be reassessed periodically. If signs/symptoms of TD occur during antipsychotic therapy, discontinuation of the offending agent should be considered; however, some patients may require treatment despite the presence of TD.

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The use of olanzapine may be associated with elevations in serum transaminase. During clinical trials, 2% of patients exposed to olanzapine experienced clinically significant ALT (SGPT) elevations (>= 3 times the upper limit of normal), compared to none in the placebo group. Jaundice did not occur in any of the affected patients, however, and liver enzymes tended to return toward baseline during treatment or following its discontinuation. The manufacturer recommends that therapy with olanzapine be administered cautiously in patients with signs and symptoms of hepatic impairment and in patients with preexisting conditions associated with limited hepatic functional reserve. Periodic assessment of serum transaminases should be performed in patients with significant hepatic disease.

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Zyprexa Zydis (brand of olanzapine orally distintegrating tablets) contains 0.34 mg and 0.45 mg of phenylalanine per each 5 mg and 10 mg tablet, respectively. The phenylalanine content should be considered when this and similar products are used in patients who must restrict their intake of phenylalanine (i.e. phenylketonurics).

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Treatment with SSRI antidepressants can cause hyponatremia. Caution should be used when treating patients with hyponatremia or at greater risk of hyponatremia such as the elderly, patients taking diuretics or who are volume depleted.

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Some SSRI antidepressants such as fluoxetine, paroxetine and sertraline may have an effect on pupil size causing dilation. This effect can potentially narrow the eye angle resulting in increased intraocular pressure and angle closure glaucoma, especially in predisposed patients. These drugs should be used with caution in patients with angle-closure glaucoma or history of glaucoma.

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Selective serotonin reuptake inhibitors (SSRIs) are primarily metabolized by the liver. The plasma concentrations of SSRIs and their metabolites may be increased and the half-lives prolonged in patients with impaired hepatic function. Dosage adjustments may be necessary in accordance with the individual product package labeling.

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Selective serotonin reuptake inhibitors (SSRIs), like other antidepressants, may occasionally cause or activate mania or hypomania. The reported incidence ranged from 0.1% to 2% in premarketing testing of several SSRIs. Patients with bipolar disorder are generally more likely to experience mania from antidepressants. Therapy with SSRIs should be administered cautiously in patients with a history of mania or bipolar disorder. Prior to initiating treatment, it is recommended to adequately screen patients for bipolar disorder, including a family history of suicide, bipolar disorder, and depression.

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The use of selective serotonin reuptake inhibitors (SSRIs) has been associated with altered platelet function. Petechiae, purpura, ecchymosis, increased bleeding times, epistaxis and gastrointestinal hemorrhage have been reported. Therapy with SSRIs should be administered cautiously in patients with severe active bleeding or a hemorrhagic diathesis.

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Some SSRI antidepressants such as fluoxetine and citalopram have shown to cause QT interval prolongation and ventricular arrhythmias including Torsade de Pointes. These drugs should be used with caution in patients with congenital QT syndrome, a previous personal or family history of QT prolongation, and ventricular arrhythmia. Consider periodic EKG assessment on these patients. Treatment should be discontinued and a cardiac evaluation should be considered if a patient develops signs or symptoms of ventricular arrhythmia.

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Selective serotonin reuptake inhibitors (SSRIs) may trigger seizures in approximately 0.2% of patients, and some of them are not recommended in patients with unstable epilepsy. Therapy with SSRIs should be administered cautiously in patients with seizure disorders.

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The use of selective serotonin reuptake inhibitors (SSRIs) has rarely been associated with hyponatremia, sometimes secondary to development of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). These events have generally been reversible following discontinuation of SSRI therapy and/or medical intervention. SSRI-related hyponatremia may be more common in elderly female patients and those who are volume-depleted or receiving concomitant diuretic therapy. Caution may be warranted when SSRI therapy is administered in these patients and patients with preexisting hyponatremia or SIADH. Serum electrolytes, especially sodium as well as BUN and plasma creatinine, should be monitored regularly.

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Fluoxetine is primarily metabolized by the liver. All but one metabolites are inactive, and they are excreted by the kidney. The clearance of norfluoxetine, the active metabolite, is not dependent on renal function. Dosage adjustments are generally not deemed necessary in patients with impaired renal function, although the clinical significance of possible metabolite accumulation is unknown. Caution may be warranted when fluoxetine therapy is administered in patients with severe renal dysfunction.

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The use of selective serotonin reuptake inhibitors (SSRIs) may occasionally cause significant weight loss, which may be undesirable in patients suffering from anorexia, malnutrition or excessive weight loss. Anorexia may occur in approximately 5% to 10% of patients. Weight change should be monitored during therapy if an SSRI is used in these patients.

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