Adasuve - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single-dose inhaler contains 5 mg loxapine and delivers 4.5 mg loxapine.

3. PHARMACEUTICAL FORM

Inhalation powder, pre-dispensed (inhalation powder).

White device with a mouthpiece on one end and a pull-tab protruding from the other end.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

ADASUVE is indicated for the rapid control of mild-to-moderate agitation in adult patients with schizophrenia or bipolar disorder. Patients should receive regular treatment immediately after control of acute agitation symptoms.

4.2 Posology and method of administration

ADASUVE should only be administered in a hospital-setting under the supervision of a healthcare professional.

Short-acting beta-agonist bronchodilator treatment should be available for treatment of possible severe respiratory side-effects (bronchospasm).

Posology

The recommended initial dose of ADASUVE is 9.1 mg. As this dose cannot be reach with this presentation (ADASUVE 4.5 mg), the presentation ADASUVE 9.1 mg should be used initially. A second dose can be given after 2 hours, if necessary. No more than two doses should be administered.

A lower dose of 4.5 mg may be given if the 9.1 mg dose was not previously tolerated by the patient or if the physician decides a lower dose is more appropriate.

Patient should be observed during the first hour after each dose for signs and symptoms of bronchospasm.

Elderly

The safety and efficacy of ADASUVE in patients older than 65 years of age have not been established. No data are available.

Renal and/or hepatic impairment

ADASUVE has not been studied in patients with renal or hepatic impairment. No data are available.

Paediatric population

The safety and efficacy of ADASUVE in children (less than 18 years of age) have not been established. No data are available.

Method of administration

Inhalation use. The product is packaged in a sealed pouch.

When needed, the product is removed from the pouch. Once the pull-tab is removed, a green light turns on, indicating the product is ready for use (Note: the product must be used within 15 minutes of pulling the tab). To deliver the medicinal product, the patient inhales through the mouthpiece with a steady deep breath. Upon completion of the inhalation, the patient removes the mouthpiece from mouth and holds breath briefly. The medicinal product has been delivered when the green light turns off. The device exterior may become warm during use. This is normal.

For complete instructions on how to use ADASUVE see information for the healthcare professional section of the package leaflet.

4.3 Contraindications

Hypersensitivity to the active substance, or to amoxapine.

Patients with acute respiratory signs/symptoms (e.g., wheezing) or with active airways disease (such as patients with asthma or chronic obstructive pulmonary disease [COPD] (see section 4.4).

4.4 Special warnings and precautions for use

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).

4.5 Interaction with other medicinal products and other forms of interaction

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).

4.6 Fertility, pregnancy and lactation

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).

4.7 Effects on ability to drive and use machines

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).

4.8 Undesirable effects

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

MedDRA system organ classification__________­________________________­______________

Nervous system disorders

Very common: sedation/somnolence

Common: dizziness

Uncommon: dystonia, dyskinesia, oculogyration, tremor, akathisia/res­tlessness

Vascular disorders

Uncommon: hypotension__________­________________________­________________________­__

Respiratory, thoracic and mediastinal disorders

Common: throat irritation

Uncommon: bronchospasm (including shortness of breath)__________­________________________

Gastrointestinal disorders

Very common: dysgeusia

Common: dry mouth__________­________________________­________________________­___

General disorders and administration site conditions

Common: fatigue

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.

4.9 Overdose

No cases of overdosage of ADASUVE were reported in clinical studies.

Symptoms

In the event of accidental overdosage, signs and symptoms will depend on the number of units taken and individual patient tolerance. As would be expected from the pharmacologic actions of loxapine, the clinical findings may range from mild depression of the CNS and cardiovascular systems to profound hypotension, respiratory depression, and unconsciousness (see section 4.4). The possibility of occurrence of extrapyramidal symptoms and/or convulsive seizures should be kept in mind. Renal failure following oral loxapine overdosage has also been reported.

Management

The treatment of overdosage is essentially symptomatic and supportive. Severe hypotension might be expected to respond to the administration of noradrenaline or phenylephrine. Adrenaline should not be used since its use in a patient with partial adrenergic blockage may further lower the blood pressure (see sections 4.4 and 4.5). Severe extrapyramidal reactions should be treated with anticholinergic antiparkinson medicinal products or diphenhydramine hydrochloride, and anticonvulsant therapy should be initiated as indicated. Additional measures include oxygen and intravenous fluids.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: psycholeptics, antipsychotics; ATC code: N05AH01

The efficacy of loxapine is proposed to be mediated through high affinity antagonism of dopamine D2 receptors and serotonin 5-HT2A receptors. Loxapine binds with noradrenergic, histaminergic, and cholinergic receptors, and its interaction with these systems may influence the spectrum of its pharmacological effects.

Changes in the level of excitability of subcortical inhibitory areas have been observed in several animal species, associated with calming effects and suppression of aggressive behaviour.

In the two Phase 3 studies patients were enrolled who had acute agitation of at least moderate level (14 or higher on Positive and Negative Syndrome Scale (PANSS) Excited Component (PEC) scale (poor impulse control, tension, hostility, uncooperativeness, and excitement). Inclusion in Study 004–301 required a diagnosis of schizophrenia. Inclusion in Study 004–302 required a diagnosis of bipolar disorder (current episode manic or mixed). Patients had significant and long-standing psychiatric disease (Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)), based on years since diagnosis and previous hospitalizations. Patients were randomised to placebo, ADASUVE 4.5 mg and ADASUVE 9.1 mg.

The mean age of randomized patients was 43.1 years in Study 004–301 and 40.8 years in Study 004–302: young adults (18–25 years old) were scarcely (7.3%) represented in either trial. Women in the schizophrenia trial were scarcely represented (26.5%), and about half of the patients were male (49.7%) in Study 004–302. About 35% of the patients with schizophrenia were taking concomitant antipsychotics at the time of dosing while approximately 13% of the patients with bipolar disorder were taking these drugs. A majority of the patients in both Phase 3 studies were smokers with about 82% of the patients with schizophrenia and 74% of the patients with bipolar disorder currently smoking.

After the first dose, a second dose was administered at least 2 hours later if the agitation had not subsided sufficiently. A third dose was administered if needed after at least 4 hours after dose 2. Rescue medication (intramuscular lorazepam) was given if medically required. Primary endpoint was absolute change in PEC score from baseline to 2 hours following Dose 1 for both doses of ADASUVE compared with placebo. Among the other endpoints were PEC and Clinical Global Impression -Improvement (CGI-I) responders at 2 hours after dose 1, and total number of patients per group who received 1, 2, or 3 doses of study medication with and without rescue medication. Responders were considered patients with a >40% decrease from baseline in the total PEC score or patients with CGI-I score of 1 (very much improved) or 2 (much improved).

Decreased agitation was evident 10 minutes after Dose 1, the first assessment time, and at all subsequent assessments during the 24 hour evaluation period, for both 4.5 mg and 9.1 mg doses in both schizophrenia and bipolar disorder patients.

Examination of population subsets (age, race, and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

For the main results, see the table below.

Main results of the pivotal efficacy studies: comparisons between ADASUVE 4.5 mg, 9.1 mg, and placebo

*= p<0.0001    += p<0.01

PEC Responders = > 40% change from PEC Baseline;

CGI-I Responders = Score of 1 (Very Much Improved) or 2 (Much Improved)

PBO = placebo SD=Standard Deviation

In a supportive Phase 2 single dose study enrolling a total of 129 patients with schizophrenia and schizoaffective disorder the decrease in PEC change after 2 hours was –5.0 for placebo, –6.7 for ADASUVE 4.5 mg, and –8.6 (p<0.001) for ADASUVE 9.1 mg. Rescue medication was administered in respectively 32.6%, 11.1 % and 14.6 % of patients.

The European Medicines Agency has waived the obligation to submit the results of studies with ADASUVE in the subset of the paediatric population from birth to less than 12 years of age for the treatment of schizophrenia and in the subset from birth to less than 10 years of age for the treatment of bipolar disorder (see section 4.2 for information on paediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies with ADASUVE in the subset of the paediatric population from 12 to less than 18 years of age for the treatment of schizophrenia and in the subset from 10 years to less than 18 years of age in bipolar disorder (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Administration of ADASUVE resulted in rapid absorption of loxapine with a median time of maximum plasma concentration (Tmax) by 2 minutes. Loxapine exposure in the first 2 hours after administration (AUC0–2h, a measure of early exposure that is relevant to the onset of therapeutic effect) was 25.6 ng*h/mL for the 4.5 mg dose and 66.7 ng*h/mL for the 9.1 mg dose in healthy subjects.

The pharmacokinetic parameters of loxapine were determined in subjects on chronic, stable antipsychotic regimens following repeat administration of ADASUVE every 4 hours for a total of 3 doses (either 4.5 mg or 9.1 mg). Mean peak plasma concentrations were similar after the first and third dose of ADASUVE, indicating minimal accumulation during the 4-hour dosing interval.

Loxapine is removed rapidly from the plasma and distributed in tissues. Animal studies following oral administration suggest an initial preferential distribution in the lungs, brain, spleen, heart and kidney. Loxapine is 96.6% bound to human plasma proteins.

Loxapine is metabolised extensively in the liver, with multiple metabolites formed. The main metabolic pathways include hydroxylation to form 8-OH-loxapine and 7-OH-loxapine, N-oxidation to form loxapine N-oxide, and de-methylation to form amoxapine. For ADASUVE, the order of metabolites observed in humans (based on systemic exposure) was 8-OH-loxapine >> loxapine N oxide > 7-OH-loxapine > amoxapine, with plasma levels of 8-OH-loxapine similar to the parent compound. 8-OH-loxapine is not pharmacologically active at the D2 receptor while the minor metabolite, 7-OH-loxapine, has high binding affinity to D2 receptors.

Loxapine is a substrate for several CYP450 isozymes; in vitro studies demonstrated that 7-OH-loxapine is formed mainly by CYPs 3A4 and 2D6, 8-OH-loxapine is formed mainly by CYP1A2, amoxapine is formed mainly by CYP3A4, 2C19, and 2C8, and loxapine N-oxide is formed by FMOs.

The potential for loxapine and its metabolites (amoxapine, 7-OH-loxapine, 8-OH-loxapine, and loxapine-N-oxide) to inhibit CYP450 – mediated drug metabolism has been examined in vitro for CYPs 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. No significant inhibition was observed. In vitro studies indicate that loxapine and 8-OH-loxapine are not inducers of CYP1A2, 2B6 or 3A4 enzymes at clinically relevant concentrations. In addition, in vitro studies indicate that loxapine and 8-OH loxapine are not inhibitors of UGT1A1, 1A3, 1A4, 2B7 and 2B15.

Loxapine excretion occurs mainly in the first 24 hours. Metabolites are excreted in the urine in the form of conjugates and in the faeces unconjugated. The terminal elimination half-life (T'/z) ranged from 6 to 8 hours.

The mean plasma loxapine concentrations following administration of ADASUVE were linear over the clinical dose range. AUC0–2h, AUCinf, and Cmax increased in a dose-dependent manner.

A population pharmacokinetic analysis that compared exposures in smokers versus non-smokers indicated that smoking, which induces CYP1A2, had a minimal effect on the exposure to ADASUVE. No dosage adjustment is recommended based on smoking status.

In female smokers exposure (AUCinf) to ADASUVE and its active metabolite 7-OH-loxapine is lower than in female non-smokers (84% vs 109% 7-OH-loxapine/Loxapine Ratio), which is probably due to an increase in loxapine clearance in smokers.

There were no important differences in the exposure or disposition of loxapine following administration of ADASUVE due to age, gender, race, weight, or body mass index (BMI).

5.3 Preclinical safety data

Non-clinical safety data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, and genotoxicity, except for changes to reproductive tissues related to the extended pharmacology of loxapine. Similar changes, e.g., gynecomastia, are known in humans, but only after long-term administration of medicines causing hyperprolacti­naemia.

Female rats did not mate due to persistent diestrus after oral treatment with loxapine. Embryo/fetal developmental and perinatal studies have shown indications of developmental delay (reduced weights, delayed ossification, hydronephrosis, hydrourether, and/or distended renal pelvis with reduced or absent papillae) as well as increased numbers of perinatal and neonatal deaths in offspring of rats treated from mid-pregnancy with oral doses below the maximum recommended human dose for ADASUVE on a mg/m2 basis (see section 4.6).

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

None

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in the original pouch until ready for use in order to protect from light and moisture.

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

The white inhaler (housing) is molded from a medical-grade polycarbonate.

Each inhaler is provided in a sealed, multilaminate aluminum foil pouch.

ADASUVE 4.5 mg is supplied in a carton of 1 or 5 units.

Not all pack-sized may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Ferrer Internacional, S.A.

Gran Vía Carlos III, 94

08028– Barcelona

España

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/823/001 (5 single-dose inhalers)

EU/1/13/823/003 (1 single-dose inhaler)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 February 2013

Date of latest renewal: