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  • CLASSES

    First Generation Antipsychotics

    BOXED WARNING

    Acute bronchospasm, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary disease, requires a specialized care setting

    Loxapine inhalation powder (Adasuve) can cause acute bronchospasm, potentially leading to respiratory distress and respiratory arrest; therefore, it must be administered by a healthcare professional. Administration of inhalational loxapine requires a specialized care setting which has immediate on-site access to supplies and personnel trained to manage acute bronchospasm and ready access to emergency response services. Loxapine for oral inhalation (Adasuve) is contraindicated in patients with a current diagnosis or history of asthma, chronic obstructive pulmonary disease (COPD) (e.g., emphysema), or other pulmonary disease associated with bronchospasm. Use with caution in any patient with other types of pulmonary disease. The drug is also contraindicated in patients with current acute respiratory signs or symptoms (e.g., wheezing, acute bronchospasm, dyspnea) or those currently receiving medications for airway diseases such as asthma or COPD. Do not use inhalational loxapine in patients who have a history of bronchospasm after receiving the drug. Due to the risk of bronchospasm, inhalational loxapine is only available through the Adasuve Risk Evaluation and Mitigation Strategy (ADASUVE REMS) program. Healthcare facilities administering inhalational loxapine must be enrolled in ADASUVE REMS. Certified facilities must have a short-acting bronchodilator including a nebulizer and inhalation solution, for immediate treatment of bronchospasm and ready access to emergency response services. Prior to administration, all patients should be screened for a current diagnosis or history of pulmonary disease associated with bronchospasm and use of medications to treat airway disease, and examined for respiratory abnormalities (including auscultation). After use, patients should be monitored for signs and symptoms of bronchospasm or other respiratory distress, including physical exam with chest auscultation, at least every 15 minutes for a minimum of one hour. Sedation caused by loxapine can mask the symptoms of bronchospasm. All patients should be advised of the risk of bronchospasm, and instructed to seek medical assistance if they develop respiratory symptoms such as wheezing, shortness of breath, chest tightness, or cough after receiving inhalational loxapine.

    Dementia, geriatric, stroke

    Geriatric patients may be more susceptible to the actions and adverse effects of conventional antipsychotics, including tardive dyskinesia, dystonias, orthostatic hypotension, anticholinergic effects, and risk for falls and fractures. Initiate treatment with lower doses followed by careful dosage titration and close monitoring. Placebo-controlled studies of short-term use of loxapine inhalation in patients with agitation associated with schizophrenia or bipolar disorder did not include geriatric patients over 65 years of age. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients and the use of loxapine in this population should be avoided if possible due to an increase in morbidity and mortality in elderly patients with dementia receiving antipsychotics. Deaths have typically resulted from heart failure, sudden death, or infections. An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatal events, has also been reported. The Beers Criteria consider antipsychotics to be potentially inappropriate medications (PIMs) in elderly patients and use should be avoided except for treating schizophrenia or bipolar disorder. The Beers panel recommends avoiding loxapine in geriatric patients with delirium, dementia, lower urinary tract symptoms/benign prostatic hyperplasia in men, or Parkinson's disease. Non-pharmacological strategies are first-line options for treating delirium- or dementia-related behavioral problems unless they have failed or are not possible and the patient is a substantial threat to self or others. If antipsychotic use is necessary in geriatrics with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk strategies. Due to the potential for antipsychotic-induced hyponatremia and SIADH, sodium levels should be closely monitored when loxapine is initiated and after dose changes. According to the federal Omnibus Budget Reconciliation Act (OBRA) regulations in residents of long-term care facilities, antipsychotic therapy should only be initiated in a patient with behavioral or psychological symptoms of dementia (BPSD) when the patient is a danger to self or others or has symptoms due to mania or psychosis. For acute conditions persisting beyond 7 days, appropriate non-pharmacologic interventions must be attempted, unless clinically contraindicated and documented. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Antipsychotics are subject to periodic review for effectiveness, medical necessity, gradual dose reduction (GDR), or rationale for continued use. Refer to the OBRA guidelines for complete information.

    DEA CLASS

    Rx

    DESCRIPTION

    Conventional non-phenothiazine antipsychotic
    Oral formulation approved for the treatment of schizophrenia
    Inhalational formulation approved for treating agitation associated with schizophrenia or bipolar I disorder
    Inhalational loxapine is only available through a REMS program due to the risk of bronchospasm, which may result in respiratory distress or respiratory arrest

    COMMON BRAND NAMES

    ADASUVE, Loxitane

    HOW SUPPLIED

    ADASUVE/Loxapine Respiratory (Inhalation) Inhalant: 10mg
    Loxapine Succinate/Loxitane Oral Cap: 5mg, 10mg, 25mg, 50mg

    DOSAGE & INDICATIONS

    For the treatment of schizophrenia.
    Oral dosage
    Adults

    10 mg PO twice daily initially. Titrate fairly rapidly during the first 7 to 10 days according to response and tolerability. For severe cases, an initial dose of 50 mg/day PO may be necessary. Because geriatric patients may be more susceptible to the adverse effects of loxapine (e.g., anticholinergic effects, orthostatic hypotension), a lower initial dose and slower titration are advisable. The usual maintenance dose is 60 mg/day to 100 mg/day PO, which may be given as a single bedtime dose or divided twice daily, or rarely divided 3 or 4 times per day. Use of higher doses may be beneficial in selected patients. A therapeutic benefit has been observed in many patients receiving 20 mg/day to 60 mg/day. Max: 250 mg/day PO.

    For the treatment of acute agitation associated with schizophrenia or bipolar disorder (bipolar I disorder).
    Oral inhalation dosage
    Adults

    10 mg as a single dose administered by oral inhalation. Max: 10 mg single dose/24 hours. After use, monitor the patient for signs and symptoms of bronchospasm or other respiratory distress, including a physical exam with chest auscultation, at least every 15 minutes for a minimum of 1 hour. This product should only be administered by a healthcare professional and within a healthcare facility enrolled in the ADASUVE REMS program. Prior to administration, screen all patients for a current diagnosis or history of pulmonary disease associated with bronchospasm and use of medications to treat airway disease, and examine for respiratory abnormalities.

    For the treatment of severe behavioral or psychological symptoms of dementia† (BPSD)†.
    Oral dosage
    Geriatric Adults

    Initially 5 mg to 10 mg PO once daily or twice daily. Gradually titrate by no more than 5 to 10 mg/day every 4 to 7 days as needed and tolerated. As dosages increase, administer daily dosages in divided doses (2 or 3 times per day) as needed to control symptoms and limit adverse effects. Antipsychotics are not FDA-approved for this indication and the labeling of all antipsychotics contains a boxed warning noting an increased risk of death in geriatric patients being treated for behavioral problems associated with dementia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antipsychotics in long-term care facility (LTCF) residents with dementia-related behavioral symptoms. OBRA Max: 10 mg/day PO in residents meeting the OBRA criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. In addition, the facility must attempt a gradual dose reduction (GDR) in 2 separate quarters, at least 1 month apart, within the first year of admission to the facility or after the facility has initiated an antipsychotic, unless clinically contraindicated. After the first year, a GDR must be attempted annually unless clinically contraindicated. The GDR may be considered clinically contraindicated if the target symptoms returned or worsened after the most recent GDR attempt within the facility and the physician has documented justification for why attempting additional dose reductions at that time would likely impair the resident's function or increase distressed behavior.

    For the treatment of irritability associated with autistic disorder† as add-on therapy.
    Oral dosage
    Adults and Adolescents

    Data are preliminary; not FDA-approved; more studies needed. Initially, 5 mg PO every other day added to current treatments, then titrated to effect up to 15 mg PO once daily (while decreasing other medications to lower doses if possible). Max: 15 mg/day PO as add-on treatment. An open label trial studied this regimen in autistic adolescents and adults (13 to 39 years, n = 16) with Aberrant Behavior Checklist-Irritability (ABC-I) subscale scores greater than 14. The primary outcome was the Clinical Global Impressions-Improvement subscale (CGI-I) ratings of Much Improved or Very Much Improved. Twelve patients completed all visits. Median final loxapine dose was 7.5 mg/day (2.5 to 15 mg/day). All subjects were rated as Much Improved on CGI-I at 12 weeks. Mean change on ABC-I was -31%, with a p value of 0.01 at 12 weeks. Side effects were minimal (prolactin elevation occurred in 1 subject), and some patients achieved weight loss (reduced BMI and improved metabolic profiles) due to ability to dose reduce concomitant medications.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    100 mg/day PO for outpatients; up to 250 mg/day PO for severe symptoms; single 10 mg dose per 24-hour period for oral inhalation formulation.

    Geriatric

    100 mg/day PO for outpatients; up to 250 mg/day PO for severe symptoms; single 10 mg dose per 24-hour period for oral inhalation formulation.

    Adolescents

    Safety and efficacy have not been established; literature suggests up to 15 mg/day PO off-label for irritability due to autism as add-on therapy.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Although specific dosage guidelines are not available for oral loxapine, adjustments may be needed depending upon clinical response and the degree of hepatic impairment due to extensive metabolism of loxapine in the liver. According to the product labeling for inhalational loxapine, dosage adjustments are generally not required based upon hepatic function.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Administer tablets or capsules orally.

    Inhalation Administration
    Oral Inhalation Administration

    General Information
    Due to the risk of bronchospasm, loxapine for oral inhalation (Adasuve) has restricted availability only through the Adasuve Risk Evaluation and Mitigation Strategy (ADASUVE REMS) program.
    Loxapine for oral inhalation must be administered by a healthcare professional, and in a healthcare facility enrolled in the ADASUVE REMS program and with immediate on-site access to supplies and personnel trained to manage acute bronchospasm and with ready access to emergency response services. In addition, certified facilities must have a short-acting bronchodilator (including a nebulizer and inhalation solution), for the immediate treatment of bronchospasm.
    Prior to administration, all patients must be screened for a current diagnosis or history of asthma, COPD, or other pulmonary disease and use of medications to treat airway disease, and examined (including chest auscultation) for respiratory abnormalities such as wheezing.
    Each inhaler is for single use only.
    Because clinical trials in patients with asthma or COPD showed that the degree of bronchospasm was greater after a second dose, use of inhalational loxapine should be limited to a single dose per 24-hour period.
     
    Inhalation Administration
    Step 1: When ready to use, tear open pouch and remove inhaler. The indicator light on the inhaler should be off.
    Step 2: Firmly pull the plastic tab from rear of inhaler and ensure the green light turns on, which indicates the inhaler is ready to use.
    Step 3: Inform the patient that the inhaler may produce a flash of light and clicking sound, and may become warm during use.
    Step 4: Instruct the patient to hold the inhaler away from the mouth and breathe out fully to empty the lungs.
    Step 5: The patient should place the mouthpiece of the inhaler between the lips, close the lips, and inhale through the mouthpiece with a steady deep breath.
    Step 6: Instruct the patient to remove the inhaler from the mouth and hold their breath for as long as possible up to 10 seconds.
    Step 7: Check that green light turns off, indicating that the dose was delivered. If the light remains on, then step 4, step 5, and step 6 should be repeated up to 2 additional times. If the green light does not turn off, discard the inhaler and use a new one.
    Use inhaler within 15 minutes after removing the tab to prevent automatic deactivation.
    The green light will turn off after use at which time the inhaler is no longer usable.
    After use, the patient must be monitored for signs and symptoms of bronchospasm or other respiratory distress, including a physical exam with chest auscultation, at least every 15 minutes for a minimum of one hour.
    Refer to the Important Administration Instructions section of the product labeling for visual aides which accompany the written instructions.

    STORAGE

    ADASUVE:
    - Store at room temperature (between 59 to 86 degrees F)
    - Store in original package until time of use
    Loxitane:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Loxapine is contraindicated in patients with a hypersensitivity to loxapine or other dibenzoxazepines (e.g., amoxapine).

    CNS depression, coma, ethanol intoxication, overdose

    Loxapine is contraindicated in patients who are in a coma. Loxapine is contraindicated in patients with severe drug-induced CNS depression (e.g., acute severe ethanol intoxication, barbiturate or narcotics overdose, etc.).

    Coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion

    Loxapine can cause drowsiness. Patients receiving loxapine should be advised to avoid driving or operating machinery until the effects of the drug are known. Somnolence from antipsychotic therapy could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate somnolence. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Given the primary CNS effects of loxapine, caution should be used during coadministration with other CNS depressants and alcohol. Ethanol ingestion may further impair cognitive and motor skills and patients should be advised to avoid use of alcoholic beverages.

    Cardiac disease, cerebrovascular disease, heart failure, hypotension, hypovolemia, myocardial infarction, orthostatic hypotension, syncope

    Increased pulse rates have been reported in the majority of patients receiving antipsychotic loxapine oral doses; transient hypotension has been reported. Secondary to alpha-blockade, loxapine (oral and inhalational) can produce vasodilation, which may result in hypotension, orthostatic hypotension, and syncope. Therefore, cautious use is advisable in patients with cardiac disease including history of myocardial infarction, ischemic heart disease, heart failure, conduction abnormalities, cerebrovascular disease, or conditions that may predispose to hypotension (e.g., dehydrated state, hypovolemia, or treatment with antihypertensives). Orthostatic hypotension could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate orthostasis. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. If vasopressor therapy is needed for severe hypotension, norepinephrine or phenylephrine are considered preferred treatments. Epinephrine should be avoided since beta stimulation by epinephrine may worsen hypotension related to alpha-blockade by loxapine. Monitoring of orthostatic vital signs should be considered in patients for whom hypotension is a concern. Patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider dose reduction if hypotension occurs.

    Tardive dyskinesia

    Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotics. Regular evaluation for movement disorders is recommended (e.g., AIMS, DISCUS). Factors associated with a greater susceptibility to tardive dyskinesia include an age above 55 years, female gender, white or African ethnicity, presence of a mood disorder, intellectual disability, CNS injury, prior or current akathisia, significant parkinsonism, or acute dystonic reaction. The rate of tardive dyskinesia in adults treated with a first generation antipsychotic appears to be at least 3 times that observed with second generation antipsychotics. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotics administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief periods at low doses or may arise after drug discontinuation. Antipsychotics may suppress the signs and symptoms of tardive dyskinesia and thereby mask the underlying process; however, the syndrome may also remit partially or completely if the antipsychotic is withdrawn. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. If signs and symptoms of tardive dyskinesia appear, loxapine discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

    Ambient temperature increase, dehydration, hyperthermia, hypothermia, strenuous exercise

    Antipsychotics have been reported to disrupt the body's ability to reduce core body temperature presumably through effects in the hypothalamus, and they predispose patients to hyperthermia. Patients receiving loxapine should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, or dehydration). A less frequently described alteration in thermoregulatory processes reported with both conventional and atypical antipsychotics is hypothermia. Thermoregulation is multi-factorial; however, the dopaminergic system appears to have a primary role, and serotonin may also have modulatory activity (5-HT2a receptors). Most cases of hypothermia associated with antipsychotics have occurred in conjunction with other potential precipitating factors such as hypothyroidism, sepsis, organic brain injury, or environmental temperature. Hypothermia appears to occur more frequently during initiation of antipsychotic therapy or after dose increases.

    Seizure disorder, seizures

    Loxapine lowers the seizure threshold. Seizures have occurred in patients treated with oral loxapine at antipsychotic dosages. Seizures can occur in patients with a seizure disorder even with adequate antiepileptic drug maintenance therapy. In short term (24 hour), placebo-controlled trials of loxapine inhalation, there were no reports of seizures.

    Hepatic disease

    Loxapine is extensively metabolized by the liver. Although there are no specific guidelines available by the manufacturer of oral loxapine for patients with hepatic disease, caution is advisable. Dosage adjustments may be needed depending on clinical response and the degree of hepatic impairment. According to the product labeling for inhalational loxapine, dosage adjustments are generally not required based upon hepatic function.

    Closed-angle glaucoma

    The anticholinergic activity of loxapine has the potential to exacerbate closed-angle glaucoma; therefore, loxapine should be used cautiously in patients with this condition. The possibility of ocular toxicity from loxapine cannot be excluded at this time. Therefore, 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. It is advisable for patients on prolonged therapy with loxapine to undergo periodic ophthalmological examinations.

    Anticholinergic medications, prostatic hypertrophy, urinary retention

    Because of possible anticholinergic action, loxapine should be used cautiously in patients with a tendency to urinary retention (e.g., men with benign prostatic hypertrophy), particularly with concomitant administration of anticholinergic-type antiparkinson medication or other anticholinergic medications.

    Agranulocytosis, leukopenia, neutropenia

    Loxapine should be used with caution in patients with risks for neutropenia. Hematologic effects including leukopenia, neutropenia, and agranulocytosis (severe neutropenia) have been associated with antipsychotic use. A history of drug-induced leukopenia or neutropenia or pre-existing low white blood cell (WBC) count may increase the likelihood of developing hematologic effects during treatment with an antipsychotic medication. Patients with a history of clinically significant low WBC count or drug-induced leukopenia/neutropenia should have frequent complete blood count (CBC) assessments during the first few months of treatment. Discontinuation of the antipsychotic should be considered if a clinically significant decline in WBC occurs in the absence of an identifiable cause. Patients with clinically significant neutropenia should be closely monitored for fever and infection, and appropriate medical intervention should be instituted if necessary. Loxapine should be discontinued in patients with severe neutropenia (ANC less than 1,000/mm3); ongoing monitoring of the WBC is recommended until the symptoms resolve.

    Neurological disease, Parkinson's disease

    Antipsychotics can cause motor and sensory instability, which may lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with diseases (e.g., neurological disease), conditions, or concurrent medication use that could exacerbate motor and sensory instability. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Loxapine should generally be avoided in patients with Parkinson's disease. The dopamine blockade from loxapine may worsen the preexisting Parkinson's disease.

    Acute bronchospasm, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary disease, requires a specialized care setting

    Loxapine inhalation powder (Adasuve) can cause acute bronchospasm, potentially leading to respiratory distress and respiratory arrest; therefore, it must be administered by a healthcare professional. Administration of inhalational loxapine requires a specialized care setting which has immediate on-site access to supplies and personnel trained to manage acute bronchospasm and ready access to emergency response services. Loxapine for oral inhalation (Adasuve) is contraindicated in patients with a current diagnosis or history of asthma, chronic obstructive pulmonary disease (COPD) (e.g., emphysema), or other pulmonary disease associated with bronchospasm. Use with caution in any patient with other types of pulmonary disease. The drug is also contraindicated in patients with current acute respiratory signs or symptoms (e.g., wheezing, acute bronchospasm, dyspnea) or those currently receiving medications for airway diseases such as asthma or COPD. Do not use inhalational loxapine in patients who have a history of bronchospasm after receiving the drug. Due to the risk of bronchospasm, inhalational loxapine is only available through the Adasuve Risk Evaluation and Mitigation Strategy (ADASUVE REMS) program. Healthcare facilities administering inhalational loxapine must be enrolled in ADASUVE REMS. Certified facilities must have a short-acting bronchodilator including a nebulizer and inhalation solution, for immediate treatment of bronchospasm and ready access to emergency response services. Prior to administration, all patients should be screened for a current diagnosis or history of pulmonary disease associated with bronchospasm and use of medications to treat airway disease, and examined for respiratory abnormalities (including auscultation). After use, patients should be monitored for signs and symptoms of bronchospasm or other respiratory distress, including physical exam with chest auscultation, at least every 15 minutes for a minimum of one hour. Sedation caused by loxapine can mask the symptoms of bronchospasm. All patients should be advised of the risk of bronchospasm, and instructed to seek medical assistance if they develop respiratory symptoms such as wheezing, shortness of breath, chest tightness, or cough after receiving inhalational loxapine.

    Dementia, geriatric, stroke

    Geriatric patients may be more susceptible to the actions and adverse effects of conventional antipsychotics, including tardive dyskinesia, dystonias, orthostatic hypotension, anticholinergic effects, and risk for falls and fractures. Initiate treatment with lower doses followed by careful dosage titration and close monitoring. Placebo-controlled studies of short-term use of loxapine inhalation in patients with agitation associated with schizophrenia or bipolar disorder did not include geriatric patients over 65 years of age. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients and the use of loxapine in this population should be avoided if possible due to an increase in morbidity and mortality in elderly patients with dementia receiving antipsychotics. Deaths have typically resulted from heart failure, sudden death, or infections. An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatal events, has also been reported. The Beers Criteria consider antipsychotics to be potentially inappropriate medications (PIMs) in elderly patients and use should be avoided except for treating schizophrenia or bipolar disorder. The Beers panel recommends avoiding loxapine in geriatric patients with delirium, dementia, lower urinary tract symptoms/benign prostatic hyperplasia in men, or Parkinson's disease. Non-pharmacological strategies are first-line options for treating delirium- or dementia-related behavioral problems unless they have failed or are not possible and the patient is a substantial threat to self or others. If antipsychotic use is necessary in geriatrics with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk strategies. Due to the potential for antipsychotic-induced hyponatremia and SIADH, sodium levels should be closely monitored when loxapine is initiated and after dose changes. According to the federal Omnibus Budget Reconciliation Act (OBRA) regulations in residents of long-term care facilities, antipsychotic therapy should only be initiated in a patient with behavioral or psychological symptoms of dementia (BPSD) when the patient is a danger to self or others or has symptoms due to mania or psychosis. For acute conditions persisting beyond 7 days, appropriate non-pharmacologic interventions must be attempted, unless clinically contraindicated and documented. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Antipsychotics are subject to periodic review for effectiveness, medical necessity, gradual dose reduction (GDR), or rationale for continued use. Refer to the OBRA guidelines for complete information.

    Breast cancer, hyperprolactinemia, infertility

    Antipsychotic drugs, including loxapine, elevate prolactin levels; the elevation persists during chronic administration. Hyperprolactinemia can induce infertility in both males and females. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. Antipsychotics should be used cautiously in patients with a history of breast cancer. 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.

    Neonates, pregnancy, pregnancy testing

    There are no adequate data regarding loxapine use during human pregnancy; therefore, loxapine should be used during pregnancy only when the expected benefits outweigh the potential risks to the mother and fetus. No embryotoxicity or teratogenicity was observed in studies in rats, rabbits, or dogs, but in most studies the dosage was only 2 times the maximum recommended human dose (MRHD) and in some studies it was below this dose. Renal papillary abnormalities have been noted in offspring of rats with doses of 0.6 and 1.8 mg/kg, doses which approximate the usual human dose but which are considerably below the MRHD. Neonates exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity and have ranged from self-limited to those requiring intensive care unit support and prolonged hospitalization. Neonates exhibiting signs or symptoms of extrapyramidal effects or withdrawal should be carefully monitored. The knowledge about long-term neurobehavioral effects in offspring is limited for all antipsychotic agents and requires further investigation. According to the American Psychiatric Association treatment guidelines for schizophrenia, consider pregnancy testing in women of childbearing potential prior to initiation of an antipsychotic. The National Pregnancy Registry for Psychiatric Medications is dedicated to evaluating the safety of psychiatric medications that may be taken by women during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The primary goal of this Registry is to determine the frequency of major malformations, such as heart defects, cleft lip, or neural tube defects, in babies exposed to various psychiatric drugs during pregnancy. While the research concentrates on atypical antipsychotics and antidepressant use, pregnant women using other psychiatric medications are encouraged to register. For more information, contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by phone 1-866-961-2388. It is not known if antipsychotics, through their effect on prolactin, would affect labor or obstetric delivery.

    Breast-feeding

    According to the manufacturer, it is not known if loxapine or its metabolites are excreted into human breast milk and the drug should be avoided during breast-feeding if clinically possible; excretion of loxapine and its metabolites has been noted in the milk of lactating canines. Loxapine causes elevated prolactin levels, and thus may interfere with proper lactation in some patients. Due to individual variability in response to antipsychotics, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding; however, alternate medications for consideration include atypical agents such as olanzapine or quetiapine. It should be noted that data regarding the safety of atypical antipsychotics during breast-feeding are limited and chronic administration of any antipsychotic during breast-feeding should be avoided if possible. Regardless of the antipsychotic used, the nursing infant should be closely monitored for excessive drowsiness, lethargy, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report adverse effects to the FDA.

    Children, infants

    The safety and effectiveness of loxapine in infants, children and adolescents less than 18 years of age have not been established. However, off-label use in adolescents has been reported for low-dose oral loxapine as add-on therapy for irritability due to autistic spectrum disorder. Loxapine has not been evaluated for the management of behavioral complications in patients with mental retardation, and therefore, it cannot be recommended in such patients.

    Dysphagia

    Patients with dysphagia or who are at risk for aspiration should be closely monitored while receiving loxapine. Antipsychotics have been associated with esophageal dysmotility and aspiration of gastric contents, which may increase the incidence of aspiration pneumonia in susceptible patient populations, such as those with severe Alzheimer's disease.[54413]

    ADVERSE REACTIONS

    Severe

    bronchospasm / Rapid / 0-54.0
    seizures / Delayed / 0-1.0
    agranulocytosis / Delayed / 0-1.0
    akinesia / Delayed / Incidence not known
    neuroleptic malignant syndrome / Delayed / Incidence not known
    tardive dyskinesia / Delayed / Incidence not known
    water intoxication / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    retinopathy / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    stroke / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known

    Moderate

    orthostatic hypotension / Delayed / 1.0-10.0
    hypotension / Rapid / 1.0-10.0
    constipation / Delayed / 1.0-10.0
    hypertension / Early / 0-1.0
    galactorrhea / Delayed / 0-1.0
    hyperprolactinemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    akathisia / Delayed / Incidence not known
    dystonic reaction / Delayed / Incidence not known
    pseudoparkinsonism / Delayed / Incidence not known
    confusion / Early / Incidence not known
    dysarthria / Delayed / Incidence not known
    urinary retention / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hyponatremia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    dysphagia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    hyperthermia / Delayed / Incidence not known

    Mild

    dysgeusia / Early / 14.0-14.0
    insomnia / Early / 1.0-10.0
    dizziness / Early / 1.0-10.0
    throat irritation / Early / 3.0-3.0
    menstrual irregularity / Delayed / 0-1.0
    amenorrhea / Delayed / 0-1.0
    gynecomastia / Delayed / 0-1.0
    drowsiness / Early / 10.0
    xerostomia / Early / 10.0
    tremor / Early / Incidence not known
    agitation / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    nasal congestion / Early / Incidence not known
    syncope / Early / Incidence not known
    polydipsia / Early / Incidence not known
    fever / Early / Incidence not known
    purpura / Delayed / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    seborrhea / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    ptosis / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    weight gain / Delayed / Incidence not known
    nausea / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    cough / Delayed / Incidence not known
    hypothermia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of opioid agonists like codeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists like dihydrocodeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Acetaminophen; Chlorpheniramine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Acetaminophen; Codeine: (Moderate) Concomitant use of opioid agonists like codeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine.
    Acetaminophen; Diphenhydramine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of opioid agonists, such as oxycodone, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Acetaminophen; Tramadol: (Moderate) Concomitant use of opioid agonists with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Also, concomitant use of tramadol increases the seizure risk in patients taking loxapine.
    Acrivastine; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psyhcotropic activity. Use with caution.
    Alfentanil: (Moderate) Concomitant use of opioid agonists, such as alfentanil, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including antipsychotics, can potentiate the CNS effects of either agent.
    Amantadine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since loxapine is a dopamine antagonist, this drug is best avoided when possible in patients with Parkinson's disease who require amantadine therapy.
    Amifampridine: (Major) Carefully consider the need for concomitant treatment with loxapine and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Loxapine may increase the risk of seizures.
    Amoxapine: (Major) Amoxapine is a metabolite of loxapine and this combination is generally not prescribed. Use caution during coadministration of amoxapine and loxapine. Amoxapine exhibits some antipsychotic activity and may increase the risk of tardive dyskinesia or neuroleptic malignant syndrome (NMS) when antipsychotics are given concurrently. Clinically significant anticholinergic activity and sedation are also possible.
    Amphetamine: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Amphetamine; Dextroamphetamine Salts: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Amphetamine; Dextroamphetamine: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Anticholinergics: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Aripiprazole: (Major) Caution is advisable during concurrent use of aripiprazole with other CNS depressants such as loxapine. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Articaine; Epinephrine: (Major) Patients taking loxapine can have reduced pressor response to ephedrine, phenylephrine, metaraminol, or norepinephrine, but these drugs are preferred over epinephrine if a vasopressor agent is required. The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of loxapine. This reaction can result in an apparently paradoxical condition called 'epinephrine reversal.' Epinephrine reversal can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction.
    Asenapine: (Major) Caution is advisable during concurrent use of loxapine and other antipsychotics. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of opioid agonists like codeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists like dihydrocodeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Loxapine and orphenadrine both have anticholinergic activity. The concomitant use of these drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as orphenadrine) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Aspirin, ASA; Carisoprodol: (Moderate) Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as carisprodol) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of opioid agonists like codeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as carisprodol) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of opioid agonists, such as oxycodone, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Atropine: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with loxapine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with loxapine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Atropine; Edrophonium: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Baclofen: (Moderate) Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as baclofen) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Barbiturates: (Moderate) Loxapine can potentiate the actions of other CNS depressants, such as barbiturates. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Belladonna; Opium: (Moderate) Concomitant use of opioid agonists with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Benzhydrocodone; Acetaminophen: (Moderate) Concomitant use of opioid agonists with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Benzphetamine: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Benztropine: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Brexpiprazole: (Major) Caution is advisable during concurrent use of brexpiprazole with other antipsychotics such as loxapine. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Bromocriptine: (Major) Avoid concurrent use of loxapine and bromocriptine when possible. Loxapine, like other older antipsychotics, results in a decreased efficacy of bromocriptine. The prolactin-lowering effect of bromocriptine is antagonized; the elevation in prolactin levels produced by loxapine persists with chronic administration.
    Brompheniramine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Brompheniramine; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Brompheniramine; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Buspirone: (Moderate) The combination of buspirone and CNS depressants like the antipsychotics can increase the risk for sedation.
    Cabergoline: (Moderate) Cabergoline should not be coadministered with loxapine due to mutually antagonistic effects on dopaminergic function. The dopamine antagonist action of loxapine may diminish the prolactin-lowering ability of cabergoline while the dopamine agonist effects of cabergoline may exacerbate a psychotic disorder, reducing the effectiveness of antipsychotics such as loxapine.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and loxapine. CNS depressants can potentiate the effects of cannabidiol.
    Capsaicin; Metaxalone: (Moderate) Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as metaxolone) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Carbamazepine: (Moderate) Coadministration of carbamazepine and loxapine may result in increased serum concentrations of the active metabolite of carbamazepine, carbamazepine10,11-epoxide. Carbamazepine is metabolized to carbamazepine 10,11-epoxide by human microsomal epoxide hydrolase and loxapine inhibits of human microsomal epoxide hydrolase. In addition, loxapine lowers the seizure threshold. Seizures have been reported in patients receiving loxapine at antipsychotic dose levels, and may occur in epileptic patients even with maintenance of routine anticonvulsant drug therapy. Monitor carbamazepine serum concentrations and adjust the dose accordingly during concomitant use.
    Carbetapentane; Chlorpheniramine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine.
    Carbetapentane; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Carbetapentane; Pyrilamine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Carbidopa; Levodopa: (Major) Due to opposing effects on central dopaminergic activity, loxapine and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
    Carbidopa; Levodopa; Entacapone: (Major) Due to opposing effects on central dopaminergic activity, loxapine and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
    Carbinoxamine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Carbinoxamine; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Carbinoxamine; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Cariprazine: (Major) Avoid use of these drugs together due to duplicative therapeutic effects and additive risks for drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. Loxapine inhalation may be used for acute situations with caution. Cariprazine, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. The use of cariprazine with other antipsychotic agents, such as loxapine, would be expected to have additive risks for pharmacologic effects and adverse reactions. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during combined use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Carisoprodol: (Moderate) Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as carisprodol) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and loxapine. Concurrent use may result in additive CNS depression.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with loxapine should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with loxapine should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Cetrorelix: (Moderate) Antipsychotics cause hyperprolactinemia and should not be administered concomitantly with cetrorelix since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
    Chlophedianol; Dexbrompheniramine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine.
    Chlorcyclizine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlordiazepoxide; Clidinium: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Chlorpheniramine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of opioid agonists like codeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Dextromethorphan: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of opioid agonists like dihydrocodeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists like dihydrocodeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Chlorpromazine: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and chlorpromazine. Coadministration may increase the risk for drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures.
    Clemastine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Clobazam: (Major) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects which may be potentiated during concurrent use of conventional antipsychotics including loxapine. Antipsychotics may lower the seizure threshold and reduce the effectiveness of clobazam as an anticonvulsant.
    Clozapine: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and clozapine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Codeine: (Moderate) Concomitant use of opioid agonists like codeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Codeine; Guaifenesin: (Moderate) Concomitant use of opioid agonists like codeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists like codeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of opioid agonists like codeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) The use of promethazine, a phenothiazine antiemetic, with antipsychotics such as loxapine should be avoided if possible. Coadministration of promethazine with loxapine may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
    Codeine; Promethazine: (Moderate) Concomitant use of opioid agonists like codeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) The use of promethazine, a phenothiazine antiemetic, with antipsychotics such as loxapine should be avoided if possible. Coadministration of promethazine with loxapine may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
    COMT inhibitors: (Major) Due to opposing effects on central dopaminergic activity, loxapine and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider if an atypical antipsychotic is a potential alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
    Cyclizine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Cyclobenzaprine: (Moderate) Loxapine and cyclobenzaprine both have anticholinergic activity. The concomitant use of these drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as cyclobenzaprine) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Cyproheptadine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Dantrolene: (Moderate) Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as dantrolene) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Degarelix: (Major) Avoid coadministration of degarelix with loxapine due to the risk of reduced efficacy of degarelix. Loxapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; degarelix is a GnRH analog.
    Deutetrabenazine: (Moderate) Monitor for signs and symptoms of neuroleptic malignant syndrome (NMS), restlessness, and agitation. If NMS is diagnosed, immediately discontinue deutetrabenazine, and provide intensive symptomatic treatment and medical monitoring. Recurrence of NMS has been reported with resumption of drug therapy. If akathisia or parkinsonism develops during treatment, the deutetrabenazine dose should be reduced; discontinuation may be required. Deutetrabenazine is a reversible, dopamine depleting drug and loxapine is a dopamine antagonist. The risk for parkinsonism, NMS, or akathisia may be increased with concomitant administration. Additionally, advise patients that concurrent use of deutetrabenazine and drugs that cause CNS depression, such as loxapine, may have additive effects and worsen drowsiness or sedation.
    Dexbrompheniramine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Dexchlorpheniramine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Dextroamphetamine: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine.
    Dicyclomine: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists like dihydrocodeine with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Dimenhydrinate: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Diphenhydramine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Diphenhydramine; Ibuprofen: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Diphenhydramine; Naproxen: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Diphenhydramine; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Disopyramide: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties like disopyramide and loxapine are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    dopamine agonists: (Major) Due to opposing effects on central dopaminergic activity, loxapine and dopamine agonists may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to loxapine, if appropriate. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
    Dopamine: (Moderate) The vasoconstrictive properties of dopamine infusion can be decreased by the alpha-adrenergic blocking capability of loxapine. Dopamine infusions intended to improve renal perfusion can be ineffective due to loxapine's dopamine receptor blockade.
    Doxylamine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Doxylamine; Pyridoxine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Ephedrine: (Major) Patients taking loxapine can have reduced pressor response to ephedrine, but ephedrine is preferred over epinephrine if a vasopressor agent is required.
    Ephedrine; Guaifenesin: (Major) Patients taking loxapine can have reduced pressor response to ephedrine, but ephedrine is preferred over epinephrine if a vasopressor agent is required.
    Epinephrine: (Major) Patients taking loxapine can have reduced pressor response to ephedrine, phenylephrine, metaraminol, or norepinephrine, but these drugs are preferred over epinephrine if a vasopressor agent is required. The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of loxapine. This reaction can result in an apparently paradoxical condition called 'epinephrine reversal.' Epinephrine reversal can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction.
    Esketamine: (Moderate) Closely monitor patients receiving esketamine and loxapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
    Eszopiclone: (Moderate) A reduction in the dose of eszopiclone should be considered during co-administration of other CNS depressants, such as antipsychotics, to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Antipsychotics with a higher incidence of sedation, such as olanzapine, clozapine, quetiapine, lurasidone, chlorpromazine, and thioridazine, are more likely to interact with eszopiclone. In one evaluation, concurrent use of eszopiclone and olanzapine reduced psychomotor function as measured by the Digit Symbol Substitution Test (DSST).
    Ethanol: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Ethosuximide: (Moderate) Concomitant use of ethosuximide with loxapine can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and loxapine. Concurrent use may result in additive CNS depression.
    Fentanyl: (Moderate) Concomitant use of opioid agonists, such as fentanyl, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Flavoxate: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Fluphenazine: (Major) Caution is advisable during concurrent use of loxapine and other antipsychotics. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Food: (Major) It is recommended that patients avoid the use of marijuana, by any route, if they are treated for a psychiatric history, including psychosis and bipolar disorder, as the cannabinoids (the psychoactive ingredients, such as THC) in marijuana can produce psychotoxic effects and may exacerbate psychiatric disorders. A high frequency of use and use of products with high-potency of THC are potential risk factors for psychiatric effects. Additionally, additive CNS effects, such as sedation or CNS depression are possible. Clinical studies suggest that cannabis use may reduce the efficacy of some antipsychotic drugs. In addition, several cannabinoids in marijuana appear to influence the activity of CYP enzymes and P-glycoprotein, which may alter the concentrations of antipsychotics and influence either safety or efficacy.
    Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of loxapine and gabapentin. Concurrent use may result in additive CNS depression.
    Ganirelix: (Moderate) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with gonadotropin releasing hormone analogs since hyperprolactinemia downregulates the number of pituitary GnRH receptors.
    General anesthetics: (Moderate) Loxapine can potentiate the actions of other CNS depressants such as general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
    Glycopyrrolate: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Glycopyrrolate; Formoterol: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Goserelin: (Major) Avoid coadministration of goserelin with loxapine due to the risk of reduced efficacy of goserelin. Loxapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; goserelin is a GnRH analog.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Guaifenesin; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine.
    Haloperidol: (Major) Caution is advisable during concurrent use of loxapine and other antipsychotics. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Histrelin: (Major) Avoid coadministration of histrelin with loxapine due to the risk of reduced efficacy of histrelin. Loxapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Hydantoins: (Major) Hydantoins may induce hepatic microsomal enzymes, leading to increased clearance of antipsychotic agents including loxapine. Also, loxapine may lower the seizure threshold. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either drug.
    Hydrocodone: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine. (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists like hydrocodone with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Avoid prescribing opioid cough medication in patients taking loxapine.
    Hydromorphone: (Moderate) Concomitant use of opioid agonists, such as hydromorphone, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Hydroxyzine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Hyoscyamine: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of opioid agonists, such as oxycodone, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Iloperidone: (Major) Caution is advisable during concurrent use of loxapine and other antipsychotics. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Indacaterol; Glycopyrrolate: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Isocarboxazid: (Moderate) Due to the potential for additive CNS and cardiovascular effects such as hypotension, sedation, and anticholinergic effects, MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and loxapine. Concurrent use may result in additive CNS depression.
    Leuprolide: (Major) Avoid coadministration of leuprolide with loxapine due to the risk of reduced efficacy of leuprolide. Loxapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of leuprolide with loxapine due to the risk of reduced efficacy of leuprolide. Loxapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with loxapine should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Levodopa: (Major) Due to opposing effects on central dopaminergic activity, loxapine and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
    Levorphanol: (Moderate) Concomitant use of opioid agonists, such as levorphanol, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Lithium: (Moderate) It is advisable to monitor patients for neurotoxicity during co-administration of lithium and loxapine. Although conventional antipsychotics are considered a treatment option as adjuncts to mood stabilizers such as lithium, neuroleptic malignant syndrome (NMS) and extrapyramidal effects have been observed occasionally during concurrent use. Early case reports described an encephalopathic syndrome consisting of delirium, tremulousness, dyskinesia, seizures, leukocytosis, weakness, hyperpyrexia, confusion, extrapyramidal symptoms, elevations in laboratory values (e.g., liver function tests, blood urea nitrogen, fasting blood sugar) and, in some cases, irreversible brain damage, during use of lithium and conventional antipsychotics, particularly haloperidol. Subsequent rare reports of NMS or NMS-like reactions have been described during co-administration of lithium and atypical antipsychotics (e.g., risperidone, olanzapine, clozapine). Following resolution of NMS, there are isolated instances of re-emergence of symptoms following re-initiation of lithium as monotherapy. Lithium may be a risk factor for antipsychotic-induced NMS; however, this hypothesis has not been confirmed. In many reported cases, confounding factors have been present (e.g., previous history of NMS, high dose therapy). The ability of antipsychotics alone to precipitate NMS and the rarity of the condition further complicate assessment of lithium as a risk factor.
    Lofexidine: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and loxapine. Lofexidine can potentiate the effects of CNS depressants.
    Lorazepam: (Moderate) The combination of loxapine and lorazepam has been associated with acute respiratory depression, stupor, and/or hypotension in several patients. Lorazepam, and possibly other benzodiazepines, should be used cautiously in patients receiving loxapine.
    Lumateperone: (Moderate) Coadministration of antipsychotics, such as lumateperone and loxapine, may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from antipsychotic combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
    Lurasidone: (Major) Caution is advisable during concurrent use of loxapine and other antipsychotics. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Maprotiline: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other drugs known to possess relatively significant antimuscarinic properties including loxapine.
    Meclizine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Mepenzolate: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Meperidine: (Moderate) Concomitant use of opioid agonists, such as meperidine, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Meperidine; Promethazine: (Moderate) Concomitant use of opioid agonists, such as meperidine, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) The use of promethazine, a phenothiazine antiemetic, with antipsychotics such as loxapine should be avoided if possible. Coadministration of promethazine with loxapine may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
    Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including antipsychotics.
    Mesoridazine: (Major) Caution is advisable during concurrent use of loxapine and other antipsychotics. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Metaxalone: (Moderate) Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as metaxolone) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Methadone: (Moderate) Concomitant use of opioid agonists, such as methadone, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Methamphetamine: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Methscopolamine: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Metoclopramide: (Contraindicated) Avoid metoclopramide in patients receiving loxapine. There is a potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS). Some manufacturer labels for metoclopramide contraindicate the use of these drugs together, while others state avoidance is necessary. If these agents must be used together, monitor closely for movement disorders and additive CNS effects. There also may be additive sedation. Discontinue these medications at the first signs of dyskinesia.
    Molindone: (Major) Close monitoring is advisable during concurrent use of molindone with other antipsychotics. Because molindone shares certain pharmacological properties with other antipsychotics, additive cardiac effects (e.g., hypotension), CNS effects (e.g., drowsiness), or anticholinergic effects (e.g., constipation, xerostomia) may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Monoamine oxidase inhibitors: (Moderate) Due to the potential for additive CNS and cardiovascular effects such as hypotension, sedation, and anticholinergic effects, MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Morphine: (Moderate) Concomitant use of opioid agonists, such as morphine, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Morphine; Naltrexone: (Moderate) Concomitant use of opioid agonists, such as morphine, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Nafarelin: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Non-Ionic Contrast Media: (Major) Loxapine lower the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Norepinephrine: (Major) Patients taking loxapine can have reduced pressor response to norepinephrine.
    Olanzapine: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and olanzapine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Olanzapine; Fluoxetine: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and olanzapine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Oliceridine: (Moderate) Concomitant use of opioid agonists, such as oliceridine, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Orphenadrine: (Moderate) Loxapine and orphenadrine both have anticholinergic activity. The concomitant use of these drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as orphenadrine) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Oxybutynin: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Oxycodone: (Moderate) Concomitant use of opioid agonists, such as oxycodone, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Oxymorphone: (Moderate) Concomitant use of opioid agonists, such as oxymorphone, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Paliperidone: (Major) Avoid coadministration of antipsychotics, including loxapine and paliperidone, if possible. Coadministration may increase the risk of adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Paroxetine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties like paroxetine and loxapine are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Pemoline: (Major) Concurrent use of antipsychotics, such as loxapine, and pemoline should generally be avoided. Antipsychotics and stimulants may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. The pharmacology of pemoline is poorly understood, but the drug may block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of pemoline.
    Perphenazine: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and perphenazine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures.
    Perphenazine; Amitriptyline: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and perphenazine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures.
    Phenelzine: (Moderate) Due to the potential for additive CNS and cardiovascular effects such as hypotension, sedation, and anticholinergic effects, MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine.
    Pimozide: (Major) Concurrent use of pimozide with loxapine may increase the risk of adverse effects such as drowsiness, sedation, dizziness, orthostatic hypotension, extrapyramidal symptoms, or seizures.
    Pregabalin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of loxapine and pregabalin. Concurrent use may result in additive CNS depression.
    Prilocaine; Epinephrine: (Major) Patients taking loxapine can have reduced pressor response to ephedrine, phenylephrine, metaraminol, or norepinephrine, but these drugs are preferred over epinephrine if a vasopressor agent is required. The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of loxapine. This reaction can result in an apparently paradoxical condition called 'epinephrine reversal.' Epinephrine reversal can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction.
    Prochlorperazine: (Moderate) Caution is advisable during concurrent use of antipsychotics including prochlorperazine and loxapine. Additive effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures are possible.
    Promethazine: (Moderate) The use of promethazine, a phenothiazine antiemetic, with antipsychotics such as loxapine should be avoided if possible. Coadministration of promethazine with loxapine may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
    Promethazine; Dextromethorphan: (Moderate) The use of promethazine, a phenothiazine antiemetic, with antipsychotics such as loxapine should be avoided if possible. Coadministration of promethazine with loxapine may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
    Promethazine; Phenylephrine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) The use of promethazine, a phenothiazine antiemetic, with antipsychotics such as loxapine should be avoided if possible. Coadministration of promethazine with loxapine may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
    Propantheline: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Pseudoephedrine; Triprolidine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Pyrilamine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Quazepam: (Moderate) Concomitant administration of quazepam with CNS-depressant drugs, such as antipsychotics, can potentiate the CNS effects of either agent.
    Quetiapine: (Major) Caution is advisable during concurrent use of loxapine and other antipsychotics. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Rasagiline: (Major) Due to opposing effects on central dopaminergic activity, loxapine and rasagiline may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
    Remifentanil: (Moderate) Concomitant use of opioid agonists, such as remifentanil, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Risperidone: (Major) Caution is advisable during concurrent use of loxapine and risperidone. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and risperidone. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Rotigotine: (Major) Due to opposing effects on central dopaminergic activity, loxapine and rotigotine may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. In addition, coadministration may result in additive sedation.
    Safinamide: (Major) Due to opposing effects on central dopaminergic activity, loxapine and safinamide may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
    Scopolamine: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Sedating H1-blockers: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Selegiline: (Moderate) Due to opposing effects on central dopaminergic activity, loxapine and selegiline may interfere with the effectiveness of each other. Avoid concurrent use if possible; consider an atypical antipsychotic as an alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that are known to induce Antidiuretic Hormone Secretion (SIADH), such as antipsychotics, as these drugs may increase the risk of water retention and/or electrolyte imbalance.
    Sufentanil: (Moderate) Concomitant use of opioid agonists, such as sufentanil, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Tapentadol: (Moderate) Concomitant use of opioid agonists, such as tapentadol, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Tetrabenazine: (Major) Concurrent use of loxapine and tetrabenazine should generally be avoided since the risk of adverse effects such as drowsiness, sedation, dizziness, orthostatic hypotension, neuroleptic malignant syndrome, or extrapyramidal symptoms may be increased.
    Thalidomide: (Major) Avoid the concomitant use of thalidomide with antipsychotics due to the potential for additive sedative effects.
    Thioridazine: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and thioridazine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures.
    Thiothixene: (Major) Caution is advisable during concurrent use of loxapine and other antipsychotics. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Tizanidine: (Moderate) Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as tizanidine) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Tobacco: (Minor) Tobacco smoke contains polycyclic aromatic hydrocarbons that induce hepatic CYP450 microsomal enzymes; there is some evidence to suggest that tobacco smoke accelerates the metabolism of various antipsychotics, many of which are extensively metabolized. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, the sudden cessation of tobacco smoking may result in a reduced clearance of this antipsychotic, despite the initiation of a nicotine replacement product. Monitor patients carefully when changes in smoking status occur. Per the manufacturer, there are no clinically significant differences in loxapine inhalation kinetics based upon smoking status.
    Tramadol: (Moderate) Concomitant use of opioid agonists with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Also, concomitant use of tramadol increases the seizure risk in patients taking loxapine.
    Tranylcypromine: (Moderate) Due to the potential for additive CNS and cardiovascular effects such as hypotension, sedation, and anticholinergic effects, MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Tricyclic antidepressants: (Moderate) Use caution when combining tricyclic antidepressants (TCAs) with loxapine, which both exhibit anticholinergic activity and may cause CNS effects. Some TCAs may be more likely to cause side effects than others. Because secondary amines, such as desipramine, are generally less likely than tertiary amines (e.g., amitriptyline) to cause sedation, orthostatic hypotension, and anticholinergic effects, TCAs such as desipramine may be preferred for use with antipsychotics.
    Trifluoperazine: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and trifluoperazine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures.
    Trihexyphenidyl: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
    Triprolidine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Triptorelin: (Major) Avoid coadministration of triptorelin with loxapine due to the risk of reduced efficacy of triptorelin. Loxapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; triptorelin is a GnRH analog.
    Valproic Acid, Divalproex Sodium: (Major) Loxapine, used concomitantly with valproic acid, can increase CNS depression and also can lower the seizure threshold, requiring change in the dosage of valproic acid.
    Vigabatrin: (Major) Vigabatrin should not be used with loxapine, which is associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
    Zaleplon: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Ziprasidone: (Major) Caution is advisable during concurrent use of loxapine and other antipsychotics. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Zolpidem: (Moderate) CNS depressant drugs, including loxapine, may have cumulative effects when administered concurrently and they should be used cautiously with zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Zonisamide: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, it is not known if loxapine or its metabolites are excreted into human breast milk and the drug should be avoided during breast-feeding if clinically possible; excretion of loxapine and its metabolites has been noted in the milk of lactating canines. Loxapine causes elevated prolactin levels, and thus may interfere with proper lactation in some patients. Due to individual variability in response to antipsychotics, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding; however, alternate medications for consideration include atypical agents such as olanzapine or quetiapine. It should be noted that data regarding the safety of atypical antipsychotics during breast-feeding are limited and chronic administration of any antipsychotic during breast-feeding should be avoided if possible. Regardless of the antipsychotic used, the nursing infant should be closely monitored for excessive drowsiness, lethargy, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report adverse effects to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Loxapine blocks postsynaptic dopamine receptors in the mesolimbic system and increases dopamine turnover by blockade of the D2 somatodendritic autoreceptor. After approximately 12 weeks of chronic therapy, depolarization blockade of dopamine tracts occurs. The decrease in dopamine neurotransmission has been found to correlate with the antipsychotic effects. D2-receptor blockade is also responsible for the potent extrapyramidal effects observed with this drug. Dopamine blockade in the chemoreceptor trigger zone accounts for the antiemetic effects. Loxapine possesses moderate anticholinergic and strong alpha-adrenergic receptor blocking effects. Blockade of alpha1-adrenergic receptors produces sedation; muscle relaxation; and cardiovascular effects such as hypotension, reflex tachycardia, and minor changes in ECG patterns.

    PHARMACOKINETICS

    Loxapine is administered orally and by oral inhalation. An intramuscular formulation is no longer marketed. There is wide distribution, mainly into brain, lungs, heart, liver, and pancreas. The drug appears in the CSF. Loxapine is 96.6% bound to plasma proteins. Loxapine is extensively metabolized in the liver by hydroxylation, N-oxidation, and demethylation. It has several active metabolites, 8-hydroxyloxapine, 7-hydroxyloxapine, and undergoes demethylation to amoxapine and its hydroxy metabolites. Hydroxylation to form 8-hydroxyloxapine occurs through CYP1A2 and formation of 7-hydroxyloxapine occurs through CYP3A4 and CYP2D6. Plasma concentrations of 8-hydroxyloxapine are similar to loxapine. The half-life of oral loxapine is biphasic, with an initial half-life of 5 hours, and a terminal half-life of 19 hours. The terminal half-life of loxapine inhalation ranges from 6 to 8 hours. Insignificant amounts of unchanged drug are found in the urine and feces; most excretion of metabolites is as glucuronide or sulfate conjugates. Most of an oral dose is excreted in urine and feces within 24 hours.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP1A2, CYP2D6, CYP3A4, P-glycoprotein (P-gp)
    Multiple isoenzymes, including CYP1A2, CYP2D6, and CYP3A4, have a role in the metabolism of loxapine. In vitro data indicate that loxapine is a P-gp inhibitor. Due to multiple metabolic pathways, the risk of drug-drug interactions caused by an individual isoenzyme is minimal.

    Oral Route

    Following oral administration, loxapine is rapidly and completely absorbed from the GI tract. First-pass hepatic metabolism reduces bioavailability to roughly 30% compared with intramuscular doses. Peak serum concentrations are attained more slowly following IM administration but are similar at steady state to those attained after oral administration. After oral doses, sedative effects are seen in about 20 to 30 minutes, with peak effects in about 1.5 to 3 hours and a duration of about 12 hours. Several days of therapy are required to produce steady-state serum levels, and maximum antipsychotic effect may require weeks.

    Inhalation Route

    In vitro test conditions indicate that a 10 mg oral inhalation dose delivers 9.1 mg of loxapine out of the mouthpiece. Following oral inhalation, absorption is rapid with a median time to maximum plasma concentration of 2 minutes. Due to the very rapid absorption of loxapine after oral inhalation, there is significant variability in early plasma concentrations. Loxapine exposure in the first 2 hours after administration (AUC0 to 2 hours) was 66.7 ng x hour/mL for the 10 mg dose. The mean Cmax (+/- SD) is 257 ng/mL (+/- 219 ng/mL). The mean half-life is 7.61 hours.The mean plasma loxapine concentrations following administration were linear over the clinical dose range. The parameters AUC0 to 2 hours, AUCinf, and Cmax increased in a dose-dependent manner.