Loxapine

Clinically relevant QT prolongation does not appear to be associated with single and repeat doses of loxapine. Caution should be exercised when loxapine is administered in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products known to prolong the QT interval. The potential risk of QTc prolongation due to interaction with medicinal products known to prolong QTc interval is unknown.

Loxapine is a substrate for flavin-containing mono-oxygenases (FMOs), and for several CYP450 isozymes. Therefore, the risk of metabolic interactions caused by an effect on an individual isoform is limited. Caution should be used in patients receiving concomitant treatment with other medicinal products that are either inhibitors or inducers of these enzymes, particularly if the concomitant medicinal product is known to inhibit or induce several of the enzymes involved in loxapine metabolism. Such medicinal products may modify efficacy and safety of loxapine in an irregular manner. Concomitant use of CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin, enoxacin, propranolol and refecoxib) should be avoided, if possible.

Co-administration of loxapine and adrenaline may cause worsening of hypotension.

Given the primary CNS effects of loxapine, loxapine should be used with caution in combination with alcohol or other centrally acting medicinal products, e.g., anxiolytics, most antipsychotics, hypnotics, opiates, etc. The use of loxapine in patients with alcohol or medicinal product intoxication (either with prescribed or illicit medicinal products) has not been evaluated. Loxapine may cause severe respiratory depression if combined with other CNS-depressants.

Caution is advised if loxapine is combined with other medicinal products known to lower the seizure threshold, e.g. phenothiazines or butyrophenones, clozapine, tricyclics or selective serotonine reuptake inhibitors (SSRIs), tramadol, mefloquine.

Concomitant administration of benzodiazepines or other hypnosedatives or respiratory depressants may be associated with excessive sedation and respiratory depression or respiratory failure. If benzodiazepine therapy is deemed necessary in addition to loxapine, patients should be monitored for excessive sedation and for orthostatic hypotension.

The safety and efficacy of loxapine has not been evaluated in patients with agitation due to intoxication or physical disease (delirium). Loxapine should be used with caution in patients who are intoxicated or delirious.

Loxapine should be used with caution in patients with a history of convulsive disorders since it lowers the convulsive threshold. Seizures have been reported in patients receiving oral loxapine at antipsychotic dose levels, and may occur in epileptic patients even with maintenance of routine anticonvulsant drug therapy.

Because of anticholinergic action, loxapine should be used cautiously in patients with glaucoma or a tendency to urinary retention, particularly with concomitant administration of anticholinergic-type antiparkinson medicinal products.

Given the primary Central Nervous System (CNS) effects of loxapine, loxapine should be used with caution in patients with compromised respiration, such as hypovigilant patients or patients with CNS-depression due to alcohol or other centrally acting medicinal products, e.g., anxiolytics, most antipsychotics, hypnotics, opiates, etc..

Extrapyramidal symptoms (including acute dystonia) are known class effects for antipsychotics. Loxapine should be used with caution in patients with a known history of extrapyramidal symptoms.

No data are available on the use of loxapine in patients with underlying cardiovascular diseases. Loxapine is not recommended in patient populations with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolaemia, and treatment with antihypertensive medicinal products).

New-born infants exposed repeatedly to antipsychotics during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, monitoring of new-borns should be considered. Loxapine should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

The extent of the excretion of loxapine or its metabolites in human milk is not known. However, loxapine and its metabolites have been shown to be transported into the milk of lactating dogs. Patients should be advised not to breast feed for a period of 48 hours after receiving loxapine and discard the milk produced in the meantime.

Fertility

No loxapine specific human data on fertility are available. It is known that in humans, long-term treatment with antipsychotics may lead to loss of libido and amenorrhoea. In female rats, reproductive effects have been observed.

Loxapine has major influence on the ability to drive and use machines. Because of the potential for sedation/somnolence, fatigue, or dizziness, patients should not operate hazardous machines, including motor vehicles, until they are reasonably certain that loxapine has not affected them adversely.

Summary of the safety profile

Assessment of adverse reactions from clinical study data is based on two Phase 3 and one Phase 2A short-term (24-hour) placebo-controlled clinical trials enrolling 524 adult patients with agitation associated with schizophrenia (including 27 patients with schizoaffective disorder) or bipolar disorder, treated with loxapine 4.5 mg (265 patients) or loxapine 9.1 mg (259 patients).

In studies in agitated patients, bronchospasm was reported as an uncommon, but serious adverse reaction, while in subjects with active airways disease, bronchospasm was commonly reported and often required treatment with a short-acting beta-agonist bronchodilator. The most commonly reported adverse reactions during treatment with loxapine were dysgeusia, sedation/somnolence and dizziness (dizziness was more common after placebo treatment than loxapine treatment).

List of adverse reactions

The adverse reactions listed below are categorized using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Description of selected adverse reactions

Bronchospasm

In short-term (24-hour), placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar disorder without active airways disease, bronchospasm (which includes reports of wheezing, shortness of breath or cough) was uncommon in patients treated with loxapine. However, in placebo-controlled clinical trials in subjects with mild-to-moderate persistent asthma or moderate-to-severe COPD, adverse reactions of bronchospasm were reported very commonly. Most of these events occurred within 25 minutes of dosing, were mild to moderate in severity, and could be relieved with an inhaled bronchodilator.

Adverse reactions seen with chronic oral loxapine use

With chronic oral administration of loxapine, the reported adverse reactions include sedation and drowsiness; extrapyramidal symptoms (e.g., tremor, akathisia, rigidity, and dystonia); cardiovascular effects (e.g., tachycardia, hypotension, hypertension, orthostatic hypotension, light-headedness, and syncope); and anticholinergic effects (e.g., dry eyes, blurred vision, and urinary retention).