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Loxapine


General


Pronunciation

(LOKS a peen)


Brand Names: U.S.

  • Adasuve
  • Loxitane [DSC]

Indications


Use: Labeled Indications

Schizophrenia: IM, Oral: Treatment of schizophrenia.

Agitation associated with schizophrenia or bipolar I disorder: Inhalation: Acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.


Contraindications


Oral: Hypersensitivity to loxapine or any component of the formulation; severe drug-induced CNS depression; coma

Inhalation: Current diagnosis or history of asthma, COPD, or other lung disease associated with bronchospasm; acute respiratory symptoms or signs (eg, wheezing); current use of medications to treat airways disease, such as asthma or COPD; history of bronchospasm following loxapine treatment; known hypersensitivity to loxapine or amoxapine

Canadian labeling: Additional contraindication (not in US labeling): Oral, IM: Circulatory collapse


ALERT: U.S. Boxed Warning

Bronchospasm (Adasuve):

Loxapine can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest. Administer loxapine only in an enrolled health care facility that has immediate access onsite to equipment and personnel trained to manage acute bronchospasm, including advanced airway management (intubation and mechanical ventilation). Prior to administering loxapine, screen patients regarding a current diagnosis, history, or symptoms of asthma, chronic obstructive pulmonary disease (COPD), and other lung diseases, and examine (including chest auscultation) patients for respiratory signs. Monitor for signs and symptoms of bronchospasm following treatment with loxapine.

Because of the risk of bronchospasm, loxapine is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Loxapine REMS.

Increased mortality in elderly patients with dementia-related psychosis:

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 and 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was approximately 4.5%, compared with a rate of approximately 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Loxapine is not approved for the treatment of patients with dementia-related psychosis.


Dosing and Administration


Dosing: Adult

Schizophrenia:

Oral: Initial: 10 mg twice daily (up to 50 mg daily may be considered in severely disturbed patients), increase dose until psychotic symptoms are controlled; usual maintenance: 60-100 mg daily in divided doses 2-4 times daily; satisfactory response often observed with doses of 20-60 mg daily (maximum: 250 mg daily). Therapy should be maintained at lowest effective dose.

IM [Canadian product]: 12.5-50 mg every 4-6 hours or longer; individualize dose early in therapy; some patients respond satisfactorily to twice-daily dosing

Acute treatment of agitation associated with schizophrenia or bipolar I disorder: Inhalation: 10 mg once daily; maximum dose 10 mg per 24-hour period


Dosing: Geriatric

Reduced dosing may be indicated due to risks of adverse events associated with high-dose therapy. Refer to adult dosing.


Dosing: Renal Impairment

No dosage adjustment provided in manufacturer 's labeling.


Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer 's labeling. Canadian labeling does not recommend use in severe hepatic disease.


Reconstitution

Inhalation: Remove inhaler from foil pouch; indicator light is off. Firmly pull out the plastic tab from the rear of the inhaler. When the green indicator light turns on, the inhaler is ready for use. Administer inhaler within 15 minutes after removing the tab to prevent automatic deactivation of the inhaler. The green indicator light will turn off when deactivated indicating the inhaler is not usable.

Oral solution [Canadian product] should be mixed with orange or grapefruit juice prior to administration.


Administration

Inhalation: Must be administered only by a healthcare professional. Instruct patient to exhale fully. Use inhaler on inspiration and instruct patient to hold breath as long as possible, up to 10 seconds. Check that the green light turns off indicating the dose has been delivered. If the light remains on after the patient inhales, the full dose was not delivered. Repeat inhalation up to 2 additional times. If green light still does not turn off, discard inhaler and use a new one. Inhaler may produce a flash of light and clicking sound, and become warm with use; this is normal. Discard after one use.

Oral solution [Canadian product]: Mix prior to administration.

Solution for injection [Canadian product] is administered by IM injection. Do not administer IV


Storage

Capsules: Store at 20 ‚ °C to 25 ‚ °C (68 ‚ °F to 77 ‚ °F).

Inhalation: Store at 15 ‚ °C to 30 ‚ °C (59 ‚ °F to 86 ‚ °F).

Canadian products (not available in US): Injection solution, oral solution, tablets: Store at 15 ‚ °C to 30 ‚ °C (59 ‚ °F to 86 ‚ °F).


Dosage Forms/Strengths


Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Aerosol Powder Breath Activated, Inhalation [preservative free]:

Adasuve: 10 mg (1 ea)

Capsule, Oral:

Loxitane: 5 mg [DSC], 10 mg [DSC], 25 mg [DSC], 50 mg [DSC]

Generic: 5 mg, 10 mg, 25 mg, 50 mg


Drug Interactions

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Agents to Treat Airway Disease: May enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Amisulpride: Antipsychotic Agents may enhance the adverse/toxic effect of Amisulpride. Avoid combination

Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy

Analgesics (Opioid): Anticholinergic Agents may enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): May diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson agents. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: Loxapine may increase serum concentrations of the active metabolite(s) of CarBAMazepine. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Avoid combination

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Monitor therapy

LORazepam: Loxapine may enhance the adverse/toxic effect of LORazepam. Specifically, prolonged stupor, respiratory depression, and/or hypotension. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: Antipsychotic Agents may diminish the therapeutic effect of Piribedil [INT]. Piribedil [INT] may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Avoid combination

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to secretin. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification


Monitoring Parameters

Mental status; vital signs (as clinically indicated); weight, height, BMI, waist circumference (baseline; at every visit for the first 6 months; quarterly with stable antipsychotic dose); CBC (as clinically indicated; monitor frequently during the first few months of therapy in patients with pre-existing low WBC or history of drug-induced leukopenia/neutropenia); electrolytes and liver function (annually and as clinically indicated); fasting plasma glucose level/HbA1c (baseline, then yearly; in patients with diabetes risk factors or if gaining weight repeat 4 months after starting antipsychotic, then yearly); fasting lipid panel (baseline; repeat every 2 years if LDL level is normal; repeat every 6 months if LDL level is >130 mg/dL); changes in menstruation, libido, development of galactorrhea, erectile and ejaculatory function (yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for at least 2 weeks after introduction and for 2 weeks after any significant dose increase); tardive dyskinesia (every 6 months; high-risk patients every 3 months); visual changes (inquire yearly); ocular examination (yearly in patients >40 years; every 2 years in younger patients) (ADA 2004; Lehman 2004; Marder 2004).

Inhaler: Monitor for signs and symptoms of bronchospasm (vital signs and chest auscultation) at least every 15 minutes for at least 1 hour after administration.


Lab Test Interferences


Test Interactions

False-positives for phenylketonuria, amylase, uroporphyrins, urobilinogen


Adverse Reactions


Inhalation: Frequency not always defined.

Cardiovascular: Hypotension (3%), syncope (2%)

Central nervous system: Sedation (12%)

Gastrointestinal: Dysgeusia (14%)

Hypersensitivity: Hypersensitivity

Respiratory: Respiratory distress (includes bronchospasm, chest pain, cough, dyspnea, pharyngeal edema, wheezing; asthma patients: 54%; COPD patients: 19%), throat irritation (3%)

<1% (Limited to important or life-threatening): Extrapyramidal reaction

Oral: Frequency not defined.

Cardiovascular: ECG changes, edema, flushing (facial), hypertension, hypotension, orthostatic hypotension, syncope, tachycardia

Central nervous system: Agitation, confusion, disruption of body temperature regulation, dizziness, drowsiness, extrapyramidal reaction (akathisia, akinesia, dystonia, drug-induced parkinson 's disease, tardive dyskinesia), headache, hyperpyrexia, insomnia, neuroleptic malignant syndrome (NMS), numbness, paresthesia, sedation, seizure, slurred speech, tension, unsteady gait

Dermatologic: Alopecia, dermatitis, pruritus, seborrhea, skin photosensitivity, skin rash

Endocrine & metabolic: Amenorrhea, galactorrhea, gynecomastia, hyperprolactinemia, menstrual disease, polydipsia, weight gain, weight loss

Gastrointestinal: Constipation, nausea, paralytic ileus, vomiting, xerostomia

Genitourinary: Impotence, priapism (rare), urinary retention

Hematologic & oncologic: Agranulocytosis, leukopenia, thrombocytopenia

Hepatic: Hepatitis, increased serum ALT, increased serum AST, jaundice

Neuromuscular & skeletal: Muscle twitching, weakness

Ophthalmic: Blepharoptosis, blurred vision

Respiratory: Dyspnea, nasal congestion


Warnings/Precautions


Concerns related to adverse effects:

- Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, glaucoma, or visual problems. Relative to other antipsychotics, loxapine has a low potency of cholinergic blockade.

- Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm3.

- Bronchospasm: [US Boxed Warning]: Loxapine inhalation can cause bronchospasm that has the potential to lead to respiratory distress and arrest. Administer only in an REMS enrolled healthcare facility with immediate access to on-site equipment and personnel trained to manage acute bronchospasm including advanced airway management (intubation and mechanical ventilation). Prior to administering loxapine inhalation, screen patients regarding a current diagnosis or history of asthma, COPD, or other lung diseases associated with bronchospasm, acute respiratory symptoms or signs, current use of medications used to treat airway disease and examine patients for respiratory abnormalities. Loxapine can cause sedation, which can mask the signs of bronchospasm.

- CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

- Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (ie, Alzheimer disease) (Maddalena 2004).

- Extrapyramidal symptoms (EPS): May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia. Risk of dystonia (and possibly other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Risk of tardive dyskinesia and potential for irreversibility may be increased in elderly patients (particularly women), prolonged therapy, and higher total cumulative dose; antipsychotics may also mask signs/symptoms of tardive dyskinesia. Consider therapy discontinuation with signs/symptoms of tardive dyskinesia. Increased incidence of EPS has been observed with IM administration compared to oral administration.

- Hyperprolactinemia: Antipsychotic use has been associated with increased prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown (Lehman [APA] 2004; Pollack 1993; Wang 2002).

- Neuroleptic malignant syndrome (NMS): NMS has been associated with use of antipsychotic agents; monitor for hyperpyrexia, mental status changes, fever, muscle rigidity, and/or autonomic instability. Discontinue treatment immediately with onset of NMS; recurrence has been reported in patients rechallenged with antipsychotic therapy.

- Ocular effects: Antipsychotic use has been associated with pigmentary retinopathy, and lenticular and corneal deposits, particularly with prolonged therapy (Oshika 1995).

- Hypotension: May cause hypotension, orthostatic hypotension, and syncope; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, dehydration, hypovolemia, or concurrent medication use that may predispose to hypotension/bradycardia).

- Temperature regulation: Antipsychotic use has been associated with impaired core body temperature regulation; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects (Kerwin 2004; Kwok 2005; Martinez 2002).

Disease-related concerns:

- Cardiovascular disease: Use with caution in patients with cardiovascular disease.

- Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Loxapine is not approved for the treatment of dementia-related psychosis.

- Hepatic impairment: Canadian labeling recommends avoiding use in severe hepatic disease.

- Parkinson disease: Use with caution in patients with Parkinson disease.

- Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.

Concurrent drug therapy issues:

- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

- Elderly: In older adults, use increases the risk for developing tardive dyskinesia, particularly elderly women.

Dosage forms specific issues:

- Appropriate use: Injection [Canadian product]: Reserve injection for patients unable to tolerate oral administration; convert to oral dosage form with symptom control and ability to tolerate oral administration.


Pregnancy Risk Factor

C


Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization.


Actions


Pharmacology

Loxapine is a dibenzoxazepine antipsychotic which blocks postsynaptic mesolimbic D1 and D2 receptors in the brain, and also possesses serotonin 5-HT2 blocking activity


Absorption

Oral, IM, inhalation: Rapid and complete


Metabolism

Hepatic to glucuronide conjugates


Excretion

Urine (as metabolites); feces (as metabolites)


Onset of Action

Oral, IM: Within 30 minutes; Peak effect: 1.5-3 hours

Inhalation: 2 minutes


Duration of Action

Oral, IM: ~12 hours


Half-Life Elimination

Biphasic: Oral: Initial: 5 hours; Terminal: 19 hours; Inhalation: 6-8 hours


Protein Binding

Inhalation: ~97%


Patient and Family Education


Patient Education

- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

- Patient may experience fatigue, insomnia, constipation, dry mouth, bad taste, or pharyngitis. Have patient report immediately to prescriber signs of infection, wheezing, coughing, chest tightness, shortness of breath, abnormal movements, twitching, change in balance, dysphagia, difficulty speaking, tremors, difficulty moving, rigidity, severe dizziness, passing out, tachycardia, severe headache, illogical thinking, vision changes, eye pain, severe eye irritation, seizures, slurred speech, urinary retention, change in amount of urine passed, loss of strength and energy, bruising, bleeding, enlarged breasts, nipple discharge, sexual dysfunction, amenorrhea, agitation, signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot), or signs of tardive dyskinesia (unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; and puffing cheeks) (HCAHPS).

- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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