ADASUVE 4.5mg inhalation powder medication leaflet

ADASUVE 4.5 mg inhalation powder, pre-dispensed

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

Inhalation powder, pre-dispensed (inhalation powder).

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

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

ADASUVE should be administered in a medical setting under the direct supervision of a healthcareprofessional. Patients should be observed during the first hour after each dose for signs and symptomsof bronchospasm.

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

The recommended initial dose of ADASUVE is 9.1 mg. As this dose cannot be reach with thispresentation (ADASUVE 4.5 mg), the presentation ADASUVE 9.1 mg should be used initially. Asecond 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 orif the physician decides a lower dose is more appropriate.

The safety and efficacy of ADASUVE in patients older than 65 years of age have not been established.

No data are available.

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

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

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 lightturns on, indicating the product is ready for use (Note: the product must be used within 15 minutes ofpulling the tab). To deliver the medicinal product, the patient inhales through the mouthpiece with asteady deep breath. Upon completion of the inhalation, the patient removes the mouthpiece frommouth and holds breath briefly. The medicinal product has been delivered when the green light turnsoff. The device exterior may become warm during use. This is normal.

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

Hypersensitivity to the active substance, or to amoxapine.

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

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

Bronchospasm has been reported following administration of ADASUVE, especially in patients withasthma or COPD and was typically reported within 25 minutes after dosing (see section 4.8).

Consequently, ADASUVE is contraindicated in patients with asthma or COPD as well as patients withacute respiratory signs/symptoms (e.g., wheezing) (see section 4.3). ADASUVE has not beeninvestigated in patients with other forms of lung disease. It is recommended to observe patients duringthe first hour for signs and symptoms of bronchospasm following administration of ADASUVE.

In patients who may develop bronchospasm, treatment with a short-acting beta-agonist bronchodilator,e.g., salbutamol should be considered (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 usedwith 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, mostantipsychotics, 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 havedemonstrated that elderly patients with dementia-related psychosis are at an increased risk of deathcompared to placebo. ADASUVE is not indicated for the treatment of patients with dementia-relatedpsychosis.

Extrapyramidal symptoms (including acute dystonia) are known class effects for antipsychotics.

ADASUVE should be used with caution in patients with a known history of extrapyramidalsymptoms.

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 afterdiscontinuation of treatment.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidenceof autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiacdysrhythmia). 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.

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

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 ofmyocardial 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).

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 knowncardiovascular disease or family history of QT prolongation, and in concomitant use with othermedicinal products known to prolong the QT interval. The potential risk of QTc prolongation due tointeraction 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 lowersthe convulsive threshold. Seizures have been reported in patients receiving oral loxapine atantipsychotic dose levels, and may occur in epileptic patients even with maintenance of routineanticonvulsant drug therapy (see section 4.5).

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

Intoxication or physical disease (delirium)

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

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

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

Potential for ADASUVE to affect other medicinal products

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

Caution is advised if loxapine is combined with other medicinal products known to lower the seizurethreshold, e.g. phenothiazines or butyrophenones, clozapine, tricyclics or selective serotonine reuptakeinhibitors (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 ofother medicinal products in a clinically significant manner.

Given the primary CNS effects of loxapine, ADASUVE should be used with caution in combinationwith 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 causesevere 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 CYP450isozymes (see section 5.2). Therefore, the risk of metabolic interactions caused by an effect on anindividual isoform is limited. Caution should be used in patients receiving concomitant treatment withother medicinal products that are either inhibitors or inducers of these enzymes, particularly if theconcomitant medicinal product is known to inhibit or induce several of the enzymes involved inloxapine metabolism. Such medicinal products may modify efficacy and safety of ADASUVE in anirregular 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).

New-born infants exposed repeatedly to antipsychotics during the third trimester of pregnancy are atrisk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary inseverity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia,tremor, somnolence, respiratory distress, or feeding disorder. Consequently, monitoring of new-bornsshould be considered. ADASUVE should be used during pregnancy only if the potential benefitjustifies 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 anddiscard the milk produced in the meantime.

No loxapine specific human data on fertility are available. It is known that in humans, long-termtreatment with antipsychotics may lead to loss of libido and amenorrhoea. In female rats, reproductiveeffects have been observed (see section 5.3).

ADASUVE has major influence on the ability to drive and use machines. Because of the potential forsedation/somnolence, fatigue, or dizziness, patients should not operate hazardous machines, includingmotor vehicles, until they are reasonably certain that loxapine has not affected them adversely (seesection 4.8).

Assessment of adverse reactions from clinical study data is based on two Phase 3 and one Phase 2Ashort-term (24-hour) placebo-controlled clinical trials enrolling 524 adult patients with agitationassociated with schizophrenia or bipolar disorder.

In those studies, bronchospasm was uncommonly found. However, in specific Phase 1 clinical safetytrials in subjects with asthma or COPD, bronchospasm was commonly reported and often requiredtreatment with a short-acting beta-agonist bronchodilator. Consequently, ADASUVE iscontraindicated in patients with asthma,COPD or other active airway disease (see section 4.3).

The most commonly reported adverse reactions during treatment with ADASUVE were dysgeusia,sedation/somnolence and dizziness (dizziness was more common after placebo treatment thanloxapine treatment).

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

Very common: sedation/somnolence

Common: dizziness

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

Uncommon: hypotension

Common: throat irritation

Uncommon: bronchospasm (including shortness of breath)

Very common: dysgeusia

Common: dry mouth

Common: fatigue

Bronchospasm

In short-term (24-hour), placebo-controlled trials in patients with agitation associated withschizophrenia or bipolar disorder without active airways disease, bronchospasm and possiblesymptoms of bronchospasm (which includes reports of wheezing, shortness of breath or cough)wereuncommon in patients treated with ADASUVE. However, in placebo-controlled clinical trials insubjects with mild-to-moderate persistent asthma or moderate-to-severe COPD, adverse reactions ofbronchospasm were reported very commonly. Most of these events occurred within 25 minutes ofdosing, 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 anddrowsiness; extrapyramidal symptoms (e.g., tremor, akathisia, rigidity, and dystonia); cardiovasculareffects (e.g., tachycardia, hypotension, hypertension, orthostatic hypotension, light-headedness, andsyncope); and anticholinergic effects (e.g., dry eyes, blurred vision, and urinary retention).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

In the event of accidental overdosage, signs and symptoms will depend on the number of units takenand 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 toprofound hypotension, respiratory depression, and unconsciousness (see section 4.4). The possibilityof occurrence of extrapyramidal symptoms and/or convulsive seizures should be kept in mind. Renalfailure following oral loxapine overdosage has also been reported.

The treatment of overdosage is essentially symptomatic and supportive. Severe hypotension might beexpected to respond to the administration of noradrenaline or phenylephrine. Adrenaline should not beused 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 anticholinergicantiparkinson medicinal products or diphenhydramine hydrochloride, and anticonvulsant therapyshould be initiated as indicated. Additional measures include oxygen and intravenous fluids.

Pharmacotherapeutic group: psycholeptics, antipsychotics; ATC code: N05AH01

The efficacy of loxapine is proposed to be mediated through high affinity antagonism of dopamine D2receptors and serotonin 5-HT2A receptors. Loxapine binds with noradrenergic, histaminergic, andcholinergic receptors, and its interaction with these systems may influence the spectrum of itspharmacological effects.

Changes in the level of excitability of subcortical inhibitory areas have been observed in severalanimal 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 (14or higher on Positive and Negative Syndrome Scale (PANSS) Excited Component (PEC) scale (poorimpulse control, tension, hostility, uncooperativeness, and excitement). Inclusion in Study 004-301required a diagnosis of schizophrenia. Inclusion in Study 004-302 required a diagnosis of bipolardisorder (current episode manic or mixed). Patients had significant and long-standing psychiatricdisease (Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)), based onyears since diagnosis and previous hospitalizations. Patients were randomised to placebo, ADASUVE4.5 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 Study004-302: young adults (18-25 years old) were scarcely (7.3%) represented in either trial. Women inthe 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 concomitantantipsychotics at the time of dosing while approximately 13% of the patients with bipolar disorderwere taking these drugs. A majority of the patients in both Phase 3 studies were smokers with about82% of the patients with schizophrenia and 74% of the patients with bipolar disorder currentlysmoking.

After the first dose, a second dose was administered at least 2 hours later if the agitation had notsubsided 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 wasabsolute change in PEC score from baseline to 2 hours following Dose 1 for both doses of ADASUVEcompared 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 whoreceived 1, 2, or 3 doses of study medication with and without rescue medication. Responders wereconsidered patients with a ≥40% decrease from baseline in the total PEC score or patients with CGI-Iscore of 1 (very much improved) or 2 (much improved).

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

Examination of population subsets (age, race, and gender) did not reveal any differentialresponsiveness 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, andplacebo

Study 004-301 004-302

Patients Schizophrenia Bipolar Disorder

Treatment PBO 4.5 mg 9.1 mg PBO 4.5 mg 9.1 mg

N 115 116 112 105 104 105

Baseline 17.4 17.8 17.6 17.7 17.4 17.3

Change at 2 hr -5.5 -8.1+ -8.6* -4.9 -8.1* -9.0*post dose

SD 4.9 5.2 4.4 4.8 4.9 4.730 min post dose 27.8% 46.6% 57.1% 23.8% 59.6% 61.9%2 hr post dose 38.3% 62.9% 69.6% 27.6% 62.5% 73.3%% CGI-I35.7% 57.4% 67.0% 27.6% 66.3% 74.3%

Responders

One 46.1% 54.4% 60.9% 26.7% 41.3% 61.5%

Two 29.6% 30.7% 26.4% 41.0% 44.2% 26.0%

Three 8.7% 8.8% 7.3% 11.4% 5.8% 3.8%

Rescue 15.6% 6.1% 5.4% 21.0% 8.6% 8.6%

*= 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 andschizoaffective 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 administeredin respectively 32.6%, 11.1 % and 14.6 % of patients.

# Doses Needed CGI-I PEC PEC

Responder Responders Change

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 thetreatment of schizophrenia and in the subset from birth to less than 10 years of age for the treatment ofbipolar 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 thetreatment of schizophrenia and in the subset from 10 years to less than 18 years of age in bipolardisorder (see section 4.2 for information on paediatric use).

Administration of ADASUVE resulted in rapid absorption of loxapine with a median time ofmaximum plasma concentration (Tmax) by 2 minutes. Loxapine exposure in the first 2 hours afteradministration (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, stableantipsychotic regimens following repeat administration of ADASUVE every 4 hours for a total of 3doses (either 4.5 mg or 9.1 mg). Mean peak plasma concentrations were similar after the first and thirddose 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 oraladministration 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 mainmetabolic pathways include hydroxylation to form 8-OH-loxapine and 7-OH-loxapine, N-oxidation toform loxapine N-oxide, and de-methylation to form amoxapine. For ADASUVE, the order ofmetabolites observed in humans (based on systemic exposure) was 8-OH-loxapine >> loxapine Noxide > 7-OH-loxapine > amoxapine, with plasma levels of 8-OH-loxapine similar to the parentcompound. 8-OH-loxapine is not pharmacologically active at the D2 receptor while the minormetabolite, 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, andloxapine-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 wasobserved. In vitro studies indicate that loxapine and 8-OH-loxapine are not inducers of CYP1A2, 2B6or 3A4 enzymes at clinically relevant concentrations. In addition, in vitro studies indicate that loxapineand 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 theform of conjugates and in the faeces unconjugated. The terminal elimination half-life (T½) rangedfrom 6 to 8 hours.

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

Pharmacokinetics in special patient populations

Smokers

A population pharmacokinetic analysis that compared exposures in smokers versus non-smokersindicated 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 lowerthan in female non-smokers (84% vs 109% 7-OH-loxapine/Loxapine Ratio), which is probably due toan increase in loxapine clearance in smokers.

Demographics

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

Non-clinical safety data revealed no special hazard for humans based on conventional studies of safetypharmacology, repeat-dose toxicity, and genotoxicity, except for changes to reproductive tissuesrelated to the extended pharmacology of loxapine. Similar changes, e.g., gynecomastia, are known inhumans, 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/fetaldevelopmental and perinatal studies have shown indications of developmental delay (reduced weights,delayed ossification, hydronephrosis, hydrourether, and/or distended renal pelvis with reduced orabsent papillae) as well as increased numbers of perinatal and neonatal deaths in offspring of ratstreated from mid-pregnancy with oral doses below the maximum recommended human dose for

ADASUVE on a mg/m2 basis (see section 4.6).

None

Not applicable

3 years

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.

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.

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

Ferrer Internacional, S.A.

Gran Vía Carlos III, 9408028- Barcelona

España

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

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

Date of first authorisation: 20 February 2013

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.