loxapine inhaled (Rx)

>10%

Respiratory adverse effects in patients with COPD (19%)

Dysgeusia (14%)

Sedation (12%)

1-10%

Throat irritation (3%)

<1%

Bronchospasm (0.8%)

Akathisia (0.4%)

Neck dystonia and oculogyration (0.4%)

Contraindications

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 treatment

Known hypersensitivity (including serious skin reactions) to loxapine or amoxapine

Cautions

Can cause bronchospasm (see Black Box Warnings)

Monitor for signs and symptoms of bronchospasm following administration; perform a physical exam, including chest auscultation at least q15min for at least 1 hr after the dose

Increased mortality in elderly patients with demential-related psychosis (see Black Box Warnings)

Antipsychotic drugs can cause neuroleptic malignant syndrome; symptoms include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability; associated findings include increased CPK, rhabdomyolysis, increased urine and serum myoglobin, and renal failure

May cause hypotension, orthostatic hypotension, and syncope

Lowers seizure threshold; use caution in patients with history of seizures

May cause cognitive and motor impairment

May cause sedation and somnolence; use caution when driving or operating machinery and when coadministered with other drugs known to cause CNS depression

May cause anticholinergic adverse reactions, including exacerbation of glaucoma and urinary retention; caution when coadministered with other drugs that elicit anticholinergic effects

Increased incidence of stroke and transient ischemic attack in elderly patients with dementia-related psychosis treated with antipsychotic drugs

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics during pregnancy; healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866- 961-2388 or online at http://womensmentalhealth.org/ clinical-and-researchprograms/pregnancyregistry/

Neonates exposed to antipsychotic drugs, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery

The available data from published case reports and pharmacovigilance cases with loxapine in pregnant women are insufficient to determine a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes

There are risks to mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including loxapine during pregnancy

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder reported in neonates exposed to antipsychotic drugs, including loxapine, during third trimester of pregnancy; these symptoms have varied in severity

Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately; some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization

Animal data

• In animal reproduction studies, increased embryofetal toxicity and death in rat fetuses and offspring were observed when pregnant rats were orally administered loxapine, during period of organogenesis, at doses approximately less or equal to maximum recommended human dose (MRHD) based on mg/m2 body surface area

Lactation

There is no available information on presence of loxapine in human milk, effects on breastfed infant, or on milk production

The drug is present in milk of lactating dogs; when a drug is present in animal milk, it is likely that the drug will be present in human milk

The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for drug and any potential adverse effects on breastfed child from therapy or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Typical antipsychotic (dibenzoxazepine subclass of tricyclic antipsychotic agents); mechanism of action is unknown, but is theorized to antagonize central dopamine D2 and serotonin 5-HT2a receptors

Absorption

Peak Plasma Time: 2 minutes

Peak Plasma Concentration: 257 ng/mL

AUC: 66 ng•h/mL (0-2 hr); 188 ng•h/mL (infinity)

Distribution

Protein Bound: 96.6%

Metabolism

Metabolized extensively in the liver by hydroxylation; forms 8-OH-loxapine by CYP1A2 and forms 7-OH-loxapine by CYP3A4 and CYP2D6

Metabolized by N-oxidation to form loxapine N-oxide by flavanoid monoamine oxidases

Demethylated to form amoxapine Because there are multiple metabolic pathways, the risk of metabolic interactions caused by an effect on an individual isoform is minimal

Because there are multiple metabolic pathways, the risk of metabolic interactions caused by an effect on an individual isoform is minimal

Elimination

Half-life: 7.16 hr (range 6-8 hr)

Excretion: feces (unconjugated metabolites); urine (conjugated metabolites)