increase sedation. Modify Therapy/Monitor Closely.tramadolMonitor Closely (1)tramadol and loxapine both increase sedation. Use Caution/Monitor.tranylcypromineMonitor Closely (1)tranylcypromine, loxapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).trazodoneMonitor Closely (1)loxapine and trazodone both increase sedation. Use Caution/Monitor.triazolamMonitor Closely (1)triazolam and loxapine both increase sedation. Use Caution/Monitor.triclofosMonitor Closely (1)triclofos and loxapine both increase sedation. Use Caution/Monitor.trifluoperazineMonitor Closely (2)loxapine and trifluoperazine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor. loxapine and trifluoperazine both increase sedation. Use Caution/Monitor.trihexyphenidylMonitor Closely (3)trihexyphenidyl decreases levels of loxapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. trihexyphenidyl decreases levels of loxapine by pharmacodynamic antagonism. Use Caution/Monitor. loxapine increases effects of trihexyphenidyl by pharmacodynamic synergism. Use Caution/Monitor. Potential for additive anticholinergic effects.trimipramineMonitor Closely (1)loxapine and trimipramine both increase sedation. Use Caution/Monitor.triprolidineMonitor Closely (1)triprolidine and loxapine both increase sedation. Use Caution/Monitor.trospium chlorideMonitor Closely (3)trospium chloride decreases levels of loxapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. trospium chloride decreases levels of loxapine by pharmacodynamic antagonism. Use Caution/Monitor. loxapine increases effects of trospium chloride by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.vecuroniumMonitor Closely (3)vecuronium decreases levels of loxapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. vecuronium decreases levels of loxapine by pharmacodynamic antagonism. Use Caution/Monitor. loxapine increases effects of vecuronium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.venlafaxineMonitor Closely (1)venlafaxine, loxapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).vilazodoneMonitor Closely (1)vilazodone, loxapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).xylometazolineMonitor Closely (1)loxapine increases and xylometazoline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.yohimbineMonitor Closely (1)loxapine increases and yohimbine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.ziconotideMonitor Closely (1)loxapine and ziconotide both increase sedation. Use Caution/Monitor.ziprasidoneMonitor Closely (2)loxapine and ziprasidone both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor. loxapine and ziprasidone both increase sedation. Use Caution/Monitor.zolmitriptanMonitor Closely (1)zolmitriptan, loxapine. unspecified interaction mechanism. Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).zotepineMonitor Closely (2)loxapine and zotepine both increase antidopaminergic effects, including extrapyramidal symptoms and neuroleptic malignant syndrome. Use Caution/Monitor. loxapine and zotepine both increase sedation. Use Caution/Monitor. Frequency Not Defined Common Hypotension, orthostatic hypotension Akathisia, dizziness, drug-induced tardive dystonia, dystonia, extrapyramidal disease, parkinsonian, somnolence, tardive dyskinesia Diminished sweating Constipation, xerostomia Blurred vision Urinary retention Nasal congestion Serious Prolonged QT interval, torsades de pointes Ineffective thermoregulation, heatstroke or hypothermia (rare), neuroleptic malignant syndrome (rare), seizure (rare) Paralytic ileus (rare) Agranulocytosis (rare), disorder of hematopoietic structure (rare), leukopenia (rare), thrombocytopenia (rare) Cholestatic jaundice syndrome (rare) Drug-induced lupus erythematosus, systemic (rare) Priapism (rare) Postmarketing Reports Falls Black Box Warnings Patients with dementia-related psychosis who are treated with antipsychotic drugs are at an increased risk of death as shown in short-term controlled trials. The deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature This drug is not approved for the treatment of patients with dementia-related psychosis Bronchospasm Can cause bronchospasm with potential to lead to respiratory distress and respiratory arrest Available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ADASUVE REMS Administer only in an enrolled healthcare facility that has immediate access on site to supplies and personnel trained to manage acute bronchospasm, and ready access to emergency response services; facilities must have short-acting bronchodilator, including a nebulizer and inhalation solution, for immediate treatment of bronchospasm Before administering loxapine, screen patients a current diagnosis, history of COPD, asthma, or other lung diseases; examine patients, including chest auscultation for respiratory signs; monitor for signs and symptoms of bronchospasm following treatment with loxapine Contraindications Documented hypersensitivity; severe CNS depression; severe liver or cardiac disease, bone marrow suppression; narrow-angle glaucoma CNS depression (including coma), neuroleptic malignant syndrome (NMS), poorly controlled seizure disorder Cautions Use with extreme caution in patients with a history of convulsive disorders since it lowers convulsive threshold; seizures have been reported in patients receiving drug at antipsychotic dose levels, and may occur in epileptic patients even with maintenance of routine anticonvulsant drug therapy The drug has an antiemetic effect in animals; since this effect may also occur in man, therapy may mask signs of overdosage of toxic drugs and may obscure conditions such as intestinal obstruction and brain tumor Use with caution in patients with cardiovascular disease; increased pulse rates reported in majority of patients receiving antipsychotic doses; transient hypotension has been reported Watch for hypotension if administering IM; in the presence of severe hypotension requiring vasopressor therapy, the preferred drugs may be norepinephrine or angiotensin; usual doses of epinephrine may be ineffective because of inhibition of its vasopressor effect by the drug The possibility of ocular toxicity from therapy cannot be excluded; careful observation should be made for pigmentary retinopathy and lenticular pigmentation since these have been observed in some patients receiving certain other antipsychotic drugs for prolonged periods Because of possible anticholinergic action, the drug should be used cautiously in patients with glaucoma or a tendency to urinary retention, particularly with concomitant administration of anticholinergic-type antiparkinson medication Experience to date indicates the possibility of a slightly higher incidence of extrapyramidal effects following intramuscular administration than normally anticipated with oral formulations; increase may be attributable to higher plasma levels following intramuscular injection Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration; tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, clinical significance of elevated serum prolactin levels is unknown for most patients; an increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs; neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association In patients taking benzodiazepines, loxapine should be preceded by stopping benzodiazepine therapy for 2 weeks to avoid drug interactions capable of respiratory depression May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries; perform complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy FDA warning regarding off-label use for dementia in elderly Can cause bronchospasm that has potential to lead to respiratory distress and respiratory arrest (see BBW) Tardive dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs Although prevalence of the syndrome appears to be highest among elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown; both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses; there is no known treatment for established cases of tardive dyskinesia, although syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn Antipsychotic treatment itself, however, may suppress (or partially suppress) signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown; given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, is known to respond to antipsychotic drugs, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought; the need for continued treatment should be reassessed periodically If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered; however, some patients may require treatment despite the presence of the syndrome Neuroleptic malignant syndrome A potentially fatal symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported in association with antipsychotic drugs Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias); the diagnostic evaluation of patients with this syndrome is complicated In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (eg, pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS); other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology The management of NMS should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems for which specific treatments are available There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS; if a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered The patient should be carefully monitored since recurrences of NMS have been reported; the drug, like other antipsychotics, may impair mental and/or physical abilities, especially during first few days of therapy; therefore, ambulatory patients should be warned about activities requiring alertness (eg, operating vehicles or machinery) and about concomitant use of alcohol and other CNS depressants The drug has not been evaluated for the management of behavioral complications in patients with mental retardation, and therefore, it cannot be recommended Leukopenia, neutropenia, agranulocytosis Leukopenia/neutropenia and agranulocytosis reported temporally related to antipsychotic agents Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia Patients with a preexisting low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue therapy at first sign of a decline in WBC in absence of other causative factors Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue therapy and have their WBC followed until recovery REMS to mitigate bronchospasm Available only through restricted program under a REMS called the ADASUVE REMS Healthcare facilities that dispense and administer therapy must be enrolled and comply with REMS requirements; certified healthcare facilities must be able to provide immediate access on site to supplies and personnel trained to manage acute bronchospasm, and ready access to emergency response services Facilities must have a short-acting bronchodilator (e.g., albuterol), including nebulizers and inhalation solutions, for immediate treatment of bronchospasm Wholesalers and distributors