Adasuv

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ADASUVE (ADASUVE)

Composition:

Active substance:
loxapine;

1 dose contains 10.0 mg of loxapine base, corresponding to a delivered dose of 9.1 mg of loxapine.

Pharmaceutical form.

Powder for inhalation, metered.

Main physicochemical properties:
white plastic housing and activation tab without visible defects.

Pharmacotherapeutic group.

Agents acting on the nervous system. Psycholeptics. Antipsychotics. Diazepines, oxazepines, thiazepines and oxepines. ATC code N05AH01.

Pharmacological Properties.

Pharmacodynamics.

The efficacy of loxapine is presumed to be mediated by high-affinity antagonism at dopamine D2 receptors and serotonin 5-HT2A receptors. Loxapine binds to noradrenergic, histaminergic, and cholinergic receptors, and this interaction may influence the spectrum of its pharmacological effects.

Changes in excitability of subcortical inhibitory areas were observed in several animal species, which was associated with sedative effects and suppression of aggressive behavior.

Pharmacokinetics.

Absorption.

Following administration of Adasuve, rapid absorption of loxapine was observed; the median time to reach maximum plasma concentration (Tmax) was 2 minutes. Exposure to loxapine in healthy volunteers during the first 2 hours after administration (AUC0–2h, an early exposure parameter relevant to the onset of therapeutic effect) was 25.6 ng*h/mL following a 4.5 mg dose and 66.7 ng*h/mL following a 9.1 mg dose. Pharmacokinetic parameters of loxapine were determined in patients on stable, long-term antipsychotic therapy after multiple dosing of Adasuve every 4 hours, with a total of 3 doses (4.5 mg or 9.1 mg).

Mean maximum plasma concentrations of Adasuve after administration of the first and third doses were similar, indicating minimal drug accumulation over the 4-hour dosing interval.

Distribution.

Loxapine is rapidly cleared from plasma and distributed into body tissues.

Animal studies following oral administration indicate initial preferential distribution of the drug to the lungs, brain, spleen, heart, and kidneys. The extent of loxapine binding to human plasma proteins is 96.6%.

Biological Transformation (Metabolism).

Loxapine is extensively metabolized in the liver, forming numerous metabolites. The main metabolic pathways include hydroxylation forming 8-OH-loxapine and 7-OH-loxapine, N-oxidation forming loxapine-N-oxide, and demethylation forming amoxapine. After administration of Adasuve in humans, the following metabolite profile is observed (in order of decreasing systemic exposure): 8-OH-loxapine > loxapine-N-oxide > 7-OH-loxapine > amoxapine, with plasma levels of 8-OH-loxapine being similar to those of the parent compound. 8-OH-loxapine is not pharmacologically active at D2 receptors, whereas the minor metabolite 7-OH-loxapine has high binding affinity for D2 receptors.

Loxapine is a substrate for several CYP450 isoenzymes. In vitro studies showed that 7-OH-loxapine is formed primarily via CYP3A4 and 2D6, 8-OH-loxapine is formed primarily via CYP1A2, amoxapine is formed primarily via CYP3A4, 2C19, and 2C8, and loxapine-N-oxide is formed via flavin-containing monooxygenases (FMOs).

The potential of loxapine and its metabolites (amoxapine, 7-OH-loxapine, 8-OH-loxapine, and loxapine-N-oxide) to inhibit CYP450-mediated metabolism of drugs (CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) was evaluated in in vitro studies. No significant inhibition was observed. In vitro studies indicate that loxapine and 8-OH-loxapine are not inhibitors of UGT1A1, 1A3, 1A4, 2B7, or 2B15.

Elimination.

Loxapine is primarily eliminated within the first 24 hours. Metabolites are excreted in urine as conjugates and in feces in unconjugated form. The terminal elimination half-life (T½) ranges from 6 to 8 hours.

Linearity/Non-linearity.

The mean plasma concentration of loxapine after administration of Adasuve showed dose-proportional (linear) pharmacokinetics within the clinical dose range. AUC0–2h, AUCinf, and Cmax increased in a dose-dependent manner.

Pharmacokinetics in Special Patient Populations.

Smokers.

Population pharmacokinetic analysis comparing drug exposure in smokers and non-smokers indicated that smoking, which induces CYP1A2, has minimal impact on Adasuve exposure. Dose adjustment based on smoking status is not recommended. In female smokers, exposure (AUCinf) to Adasuve and its active metabolite 7-OH-loxapine is lower than in non-smoking women (7-OH-loxapine/loxapine ratio: 84% vs. 109%), likely due to increased loxapine clearance in smokers.

Demographic Data.

No clinically significant differences in loxapine exposure or distribution after Adasuve administration were observed based on age, sex, race, body weight, or body mass index (BMI).

Clinical Characteristics.

Indications.

For rapid control of agitation from mild to moderate severity in adult patients with schizophrenia or bipolar disorders. Patients should receive ongoing maintenance therapy immediately after resolution of acute agitation symptoms.

Contraindications.

Hypersensitivity to the active substance or to amoxapine.

Presence of acute respiratory symptoms such as stridorous breathing, or respiratory tract diseases, particularly bronchial asthma or chronic obstructive pulmonary disease (COPD) (see section "Special Warnings and Precautions").

Interaction with other medicinal products and other forms of interaction.

Concomitant use of benzodiazepines or other hypnotics/sedatives, or respiratory depressants, may be associated with increased sedation and respiratory depression or respiratory insufficiency. If concomitant therapy with benzodiazepines and loxapine is considered necessary, patients should be monitored for increased sedation and orthostatic hypotension.

When inhaled loxapine was combined with intramuscular lorazepam (at a dose of 1 mg), no significant effect on respiratory rate, pulse oximetry, blood pressure, or heart rate was observed compared to administration of each drug alone. The use of higher doses of lorazepam has not been studied. The sedative effect of the combination was additive.

Potential effect of Adasuve on other medicinal products.

Loxapine is not expected to cause clinically significant pharmacokinetic interactions with medicinal products metabolized via the cytochrome P450 (CYP450) isoenzyme system or through the uridine-5-diphosphate glucuronosyltransferase (UGT) glucuronidation pathway.

Caution should be exercised when loxapine is used concomitantly with medicinal products that lower the seizure threshold, such as phenothiazines or butyrophenones, clozapine, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), tramadol, mefloquine (see section "Special Warnings and Precautions").

In vitro studies indicate that loxapine is not a substrate of P-glycoprotein (P-gp) and does not inhibit P-gp. However, clinically significant inhibition of P-gp-mediated transport of other medicinal products by loxapine at therapeutic concentrations is not expected.

Due to the primary central nervous system (CNS) effects of loxapine, Adasuve should be used with caution when administered concomitantly with ethanol or other centrally acting medicinal products, such as anxiolytics, most antipsychotics, hypnotics, opioids, etc.

The use of loxapine in patients with alcohol intoxication or intoxication with other medicinal products (prescription or illicit) has not been evaluated. Concomitant use of loxapine with other CNS depressants may lead to severe respiratory depression (see section "Special Warnings and Precautions").

Potential effect of other medicinal products on Adasuve.

Loxapine is a substrate of flavin-containing monooxygenases (FMO) and several CYP450 isoenzymes. Therefore, the risk of metabolic interactions caused by the influence of individual isoenzymes is limited. Caution should be exercised when using concomitantly with medicinal products that are inhibitors or inducers of these enzymes, particularly if it is known that these medicinal products inhibit or induce enzymes involved in loxapine metabolism. Such medicinal products may affect the efficacy and safety of Adasuve. If possible, concomitant use of Adasuve with CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin, propranolol, and rofecoxib) should be avoided.

Adrenaline (epinephrine).

Concomitant use of loxapine and adrenaline may lead to worsening of arterial hypotension (see section "Special Warnings and Precautions").

Special precautions for use.

Proper use of the Adasuve inhaler is important to ensure delivery of the full dose of loxapine.

Healthcare professionals should ensure that patients use the inhaler correctly.

Concomitant use of other medicinal products by patients, particularly other antipsychotics, may reduce the effectiveness of Adasuve.

Bronchospasm.

Bronchospasm occurred very commonly during placebo-controlled clinical trials in patients with bronchial asthma or COPD, typically within 25 minutes after administration of the product. Therefore, appropriate monitoring of patients is required after each dose of Adasuve.

The use of Adasuve in patients with other forms of lung disease has not been studied.

If bronchospasm occurs after administration of Adasuve, it can be treated with a short-acting beta-agonist bronchodilator, such as salbutamol (see sections "Dosage and administration" and "Side effects"). Adasuve should not be re-administered to patients who develop respiratory symptoms (see section "Contraindications").

Hypoventilation of the lungs.

Due to the effect of loxapine on the central nervous system (CNS), Adasuve should be used with caution in patients with impaired respiratory function, for example, reduced responsiveness or CNS depression caused by ethanol or other centrally acting medicinal products such as anxiolytics, most antipsychotics, hypnotics, opioids, etc. (see section "Interaction with other medicinal products and other forms of interaction").

Elderly patients with psychosis associated with dementia.

The use of Adasuve in elderly patients, including those with psychosis associated with dementia, has not been studied.

Clinical studies with both atypical and typical antipsychotic medicinal products have shown that elderly patients with psychosis associated with dementia have an increased risk of mortality compared to patients receiving placebo.

Adasuve is not indicated for the treatment of patients with psychosis associated with dementia.

Extrapyramidal symptoms.

Extrapyramidal symptoms (including acute dystonia) are known effects of the class of antipsychotic drugs. Adasuve should be used with caution in patients with a history of extrapyramidal symptoms.

Tardive dyskinesia.

If symptoms of tardive dyskinesia appear in a patient treated with loxapine, consideration should be given to discontinuing therapy. These symptoms may transiently worsen or even emerge after discontinuation of treatment.

Neuroleptic malignant syndrome (NMS).

Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, changes in mental status, and signs of autonomic instability (unstable pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmia).

Additional signs may include elevated creatine phosphokinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops symptoms suggestive of NMS or presents with unexplained severe hyperthermia without other clinical features of NMS, treatment with Adasuve should be discontinued.

Arterial hypotension.

In short-term (24-hour) placebo-controlled trials in agitated patients treated with Adasuve, mild arterial hypotension was reported. If vasopressor therapy is required, norepinephrine or phenylephrine is preferred.

Epinephrine should not be used, as stimulation of beta-adrenergic receptors may worsen arterial hypotension in the presence of partial alpha-adrenergic receptor blockade induced by loxapine (see section "Interaction with other medicinal products and other forms of interaction").

Cardiovascular diseases.

Data on the use of Adasuve in patients with pre-existing cardiovascular diseases are lacking. Adasuve is not recommended for use in patients with cardiovascular diseases (e.g., myocardial infarction or ischemic heart disease, heart failure, or conduction disorders in medical history), cerebrovascular disease, or conditions where arterial hypotension may occur (e.g., dehydration, hypovolemia, or treatment with antihypertensive medicinal products).

QT interval.

Administration of a single dose of Adasuve was not associated with clinically significant prolongation of the QT interval. Caution should be exercised when administering Adasuve to patients with cardiovascular diseases or a family history of QT interval prolongation, as well as when co-administering other medicinal products that may prolong the QT interval. The potential risk of QTc prolongation due to interaction with medicinal products that may prolong the QTc interval is unknown.

Seizures.

Loxapine should be used with caution in patients with a history of seizure disorders, as it may lower the seizure threshold. Seizures have been reported in patients taking oral loxapine at doses typically used to achieve antipsychotic effect; seizures may also occur in patients with epilepsy even while adhering to their usual anticonvulsant regimen (see section "Interaction with other medicinal products and other forms of interaction").

Anticholinergic activity.

Due to its anticholinergic activity, Adasuve should be used with caution in patients with glaucoma or predisposition to urinary retention, particularly when co-administered with antiparkinsonian medicinal products of the anticholinergic type.

Intoxication or somatic illness (delirium).

The safety and efficacy of Adasuve in agitated patients due to intoxication or somatic illness (delirium) have not been evaluated. Adasuve should be used with caution in patients with intoxication or delirium (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding.

Pregnancy.

Newborns exposed to antipsychotics during the third trimester of pregnancy are at risk of developing adverse reactions, including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in severity and duration.

Cases of agitation, hypertension, hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disorders have been reported. Therefore, newborns should be monitored. Adasuve may be used during pregnancy only if the benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding.

The extent to which loxapine or its metabolites are excreted in human breast milk is unknown. However, loxapine and its metabolites have been shown to pass into the milk of dogs. Patients are advised to discontinue breastfeeding for 48 hours after administration of loxapine, and milk produced during this period should be expressed and discarded.

Fertility.

There are no data on the effect of loxapine on human fertility. It is known that long-term use of antipsychotic medicinal products may cause decreased libido and amenorrhea.

Preclinical studies have shown reproductive system effects in female animals (see "Preclinical safety data").

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of loxapine on reaction speed when driving or operating machinery have not been conducted. Due to the possibility of sedation/somnolence, fatigue, or dizziness, patients should avoid operating dangerous machinery and driving vehicles until they are certain that loxapine does not adversely affect them (see section "Side effects"). Adasuve has a significant effect on the ability to drive or operate machinery.

Method of administration and dosage.

Adasuv must be administered only in a specialized medical facility under strict medical supervision.

Bronchodilator therapy (short-acting beta-agonists) should be available in case of severe respiratory adverse reactions (bronchospasm).

For inhalation use. The patient inhales the medication through the mouthpiece by taking a slow, deep breath.

Method of using the inhaler.

The inhaler containing the medication is packaged in a pouch.

Important: Open the pouch immediately before using the inhaler.

The figure below shows the key parts of the inhaler.

Stages of preparation and use of the inhaler.

Step 1. Open the inhaler package immediately before use.

Unwrap the foil package and remove the inhaler from the package.

Step 2. Pull out the mouthpiece.

Pull the plastic mouthpiece out from the back of the inhaler. A green light (indicator) will illuminate, indicating that the inhaler is ready for use.

The medication must be used within 15 minutes after removing the mouthpiece or before the green light turns off, to prevent the automatic shutdown of the inhaler.

Step 3. Exhale.

Hold the inhaler away from the mouth and breathe out deeply.

Step 4. Inhale.

Place the mouthpiece to the mouth and inhale deeply.

IMPORTANT: ensure that the green light turns off after the patient inhales.

Step 5. Breath-holding.

Remove the mouthpiece from the mouth and hold the breath for a short period.

NOTE: if the indicator remains on after the patient has inhaled, repeat steps 3–5.

The outer part of the device may become warm during use. This is a normal phenomenon.

The recommended initial dose of Adasuv is 9.1 mg. The next dose of the medication may be administered after 2 hours if necessary. No more than 2 doses should be used.

Patients should be monitored for symptoms of bronchospasm during the first hours after administration of each dose.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Elderly patients
The safety and efficacy of Adasuv in patients over 65 years of age have not been established. Appropriate data are lacking.

Renal and/or hepatic impairment.
The use of Adasuv in patients with renal or hepatic impairment has not been studied. Appropriate data are lacking.

Children.
The safety and efficacy of Adasuv in children (under 18 years of age) have not been established. Appropriate data are lacking.

Overdose.

There were no reports of overdose with Adasuv during clinical trials.

In case of accidental overdose, symptoms will depend on the amount of medication taken and the individual patient's tolerance.

Based on the pharmacological action of loxapine, clinical manifestations may range from mild central nervous system (CNS) and cardiovascular depression to severe hypotension, respiratory depression, and unconsciousness (see section "Special precautions for use"). Extrapyramidal symptoms and/or seizures should also be considered. Renal failure has also been reported following oral overdose of loxapine.

Treatment of overdose is generally supportive and symptomatic. Severe hypotension should be considered; norepinephrine and phenylephrine may be used. Adrenaline (epinephrine) should not be administered, as its use in patients with partial adrenergic blockade may lead to a further drop in blood pressure (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use"). In cases of severe extrapyramidal reactions, anticholinergic antiparkinsonian agents or diphenhydramine hydrochloride should be administered, and anticonvulsant therapy initiated as indicated. Additional measures include oxygen inhalation and intravenous fluid administration.

Adverse Reactions

The assessment of adverse reactions is based on data from short-term (24-hour) placebo-controlled clinical trials (two Phase 3 trials and one Phase 2A trial) involving 524 adult patients with agitation associated with schizophrenia (including 27 patients with schizoaffective disorders) or bipolar disorders treated with Adasuve.

During the trials, bronchospasm was infrequently reported in patients with agitation and is considered a serious adverse reaction; however, in patients with respiratory diseases, bronchospasm was frequently reported and required treatment with bronchodilators (short-acting beta-agonists). The most commonly reported adverse reactions with Adasuve were dysgeusia, sedation/somnolence, and dizziness (dizziness was more frequently reported in the placebo group than in the loxapine group).

Adverse reactions are classified into the following frequency categories: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10,000, < 1/1000), and very rare (< 1/10,000).

Central Nervous System

Very common: Sedation/somnolence
Common: Dizziness
Uncommon: Dystonia, dyskinesia, oculogyric crisis, tremor, akathisia/restlessness

Vascular System

Uncommon: Arterial hypotension

Respiratory System

Common: Throat irritation
Uncommon: Bronchospasm (including dyspnea)

Gastrointestinal System

Very common: Dysgeusia
Common: Dry mouth

General Disorders

Common: Fatigue

Description of selected adverse reactions

Bronchospasm
During short-term (24-hour) placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar disorders and without pre-existing respiratory disease, bronchospasm (including reports of stridor, dyspnea, or cough) was infrequently reported with Adasuve. However, in placebo-controlled clinical trials in patients with mild to moderate persistent bronchial asthma or moderate to severe chronic obstructive pulmonary disease, bronchospasm was reported more frequently. Most of these reactions occurred within 25 minutes of administration and were of mild to moderate severity. Symptoms improved with inhaled bronchodilators.

Adverse reactions observed with long-term oral administration of loxapine
With chronic oral administration of loxapine, adverse reactions such as sedation and dizziness, extrapyramidal symptoms (e.g., tremor, akathisia, rigidity, and dystonia), cardiovascular effects (e.g., tachycardia, arterial hypotension, arterial hypertension, orthostatic hypotension, dizziness, syncope), and anticholinergic effects (e.g., dry eyes, blurred vision, and urinary retention) have been reported.

Reporting suspected adverse reactions
Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf life
4 years

Storage conditions
No special storage conditions required. Store in the original packaging. Keep out of reach and sight of children.

Packaging
One foil pouch containing one Staccato® inhaler in a cardboard carton.

Prescription status
Prescription only

Manufacturer
FerrerInternacional, S.A., Spain

Manufacturer's address
Joan Buscalla, 1-9, Sant Cugat del Vallès, Barcelona, 08173, Spain