ADASUVE Inhalation powder Ref.[9809] Active ingredients: Loxapine

Correct use of ADASUVE inhaler is important for administration of the full dose of loxapine. Healthcare professionals should ensure the patient will use the inhaler properly.

ADASUVE may have limited effectiveness when patients are on concomitant medicinal products, predominantly other antipsychotics.

Bronchospasm

In placebo-controlled clinical trials in subjects with asthma or COPD, bronchospasm was very commonly observed. When it occurred, it was typically reported within 25 minutes after dosing. Consequently, patients receiving ADASUVE should be observed as appropriate following dosing. ADASUVE has not been investigated in patients with other forms of lung disease. Should bronchospasm occur after treatment with ADASUVE, it can be treated with a short-acting beta-agonist bronchodilator, e.g., salbutamol (see sections 4.2 and 4.8). ADASUVE should not be re-administered in patients who develop any respiratory signs/symptoms (see section 4.3).

Hypoventilation

Given the primary Central Nervous System (CNS) effects of loxapine, ADASUVE 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. (see section 4.5).

Elderly patients with dementia-related psychosis

ADASUVE has not been studied in elderly patients, including those with dementia-related psychosis. Clinical studies with both atypical and conventional antipsychotic medicinal products have demonstrated that elderly patients with dementia-related psychosis are at an increased risk of death compared to placebo. ADASUVE is not indicated for the treatment of patients with dementia-related psychosis.

Extrapyramidal symptoms

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

Tardive dyskinesia

If signs and symptoms of tardive dyskinesia appear in a patient being treated with loxapine, discontinuation should be considered. These symptoms can temporally worsen or can even arise after discontinuation of treatment.

Neuroleptic malignant syndrome (NMS)

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, ADASUVE must be discontinued.

Hypotension

Mild hypotension was reported in short-term (24-hour), placebo-controlled trials in agitated patients administered ADASUVE. If vasopressor therapy is required, noradrenaline or phenylephrine is preferred. Adrenaline should not be used, since beta-adrenoceptor stimulation may worsen hypotension in the setting of loxapine-induced partial alpha-adrenoceptor blockade (see section 4.5).

Cardiovascular

No data are available on the use of ADASUVE in patients with underlying cardiovascular diseases. ADASUVE 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).

QT interval

Clinically relevant QT prolongation does not appear to be associated with single and repeat doses of ADASUVE. Caution should be exercised when ADASUVE 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.

Seizures/convulsions

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 (see section 4.5).

Anticholinergic activity

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

Intoxication or physical disease (delirium)

The safety and efficacy of ADASUVE has not been evaluated in patients with agitation due to intoxication or physical disease (delirium). ADASUVE should be used with caution in patients who are intoxicated or delirious (see section 4.5).

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.

A study of inhaled loxapine and intramuscular lorazepam 1 mg in combination found no significant effects on respiratory rate, pulse oximetry, blood pressure, or heart rate compared with either drug administered alone. Higher doses of lorazepam have not been studied. The effects of the combination on sedation appeared to be additive.

Potential for ADASUVE to affect other medicinal products

Loxapine is not expected to cause clinically important pharmacokinetic interactions with medicinal products that are either metabolised by cytochrome P450 (CYP450) isozymes or glucuronidated by human uridine 5'-diphosphoglucuronosyl transferases (UGTs).

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 (see section 4.4).

In vitro studies indicated that loxapine was not a substrate for P-glycoprotein (P-gp), but does inhibit P-gp. At therapeutic concentrations, however, it is not expected to inhibit P-gp-mediated transport of other medicinal products in a clinically significant manner.

Given the primary CNS effects of loxapine, ADASUVE 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 (see section 4.4).

Potential for other medicinal products to affect ADASUVE

Loxapine is a substrate for flavin-containing mono-oxygenases (FMOs), and for several CYP450 isozymes (see section 5.2). 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 ADASUVE in an irregular manner. Concomitant use of CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin, enoxacin, propranolol and refecoxib) should be avoided, if possible.

Adrenaline

Co-administration of loxapine and adrenaline may cause worsening of hypotension (see section 4.4).

Pregnancy

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. ADASUVE should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

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 (see section 5.3).

ADASUVE 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 (see section 4.8).

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 ADASUVE 4.5 mg (265 patients) or ADASUVE 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 ADASUVE were dysgeusia, sedation/somnolence and dizziness (dizziness was more common after placebo treatment than loxapine treatment).

Tabulated 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).

Table 1. Adverse reactions:

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 ADASUVE. 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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.