Adasuve · 4.6 Fertility, pregnancy and lactation · 1

HOS-155457 · has-adverse-reaction-information · PDF-Seite 7

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 or bipolar disorder. In those studies, bronchospasm was uncommonly found. However, in specific Phase 1 clinical safety trials in subjects with asthma or COPD, bronchospasm was commonly reported and often required treatment with a short-acting beta-agonist bronchodilator. Consequently, ADASUVE is contraindicated 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 than loxapine treatment). 7 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 and possible symptoms of bronchospasm (which includes reports of wheezing, shortness of breath or cough) wereuncommon 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

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HOS-155463 · has-adverse-reaction-information · PDF-Seite 19

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 or bipolar disorder. In those studies, bronchospasm was uncommonly found. However, in specific Phase 1 clinical safety trials in subjects with asthma or COPD, bronchospasn was commonly reported and often required treatment with a short-acting beta-agonist bronchodilator. Consecuently, ADASUVE is contraindicated 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 than loxapine treatment). 19 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 and possible symptoms of bronchospasm (which includes reports of wheezing, shortness of breath or cough) were 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 chron

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HOS-155453 · has-contraindication-information · PDF-Seite 3

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).

HOS-155459 · has-contraindication-information · PDF-Seite 15

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).

HOS-155458 · has-indication-information · PDF-Seite 14

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.

HOS-155452 · has-indication-information · PDF-Seite 2

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.

HOS-155461 · has-interaction-information · PDF-Seite 17

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 17 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 en

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HOS-155455 · has-interaction-information · PDF-Seite 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 5 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 enz

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HOS-155462 · has-pregnancy-information · PDF-Seite 19

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).

HOS-155456 · has-pregnancy-information · PDF-Seite 7

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).

HOS-155454 · has-warning-information · PDF-Seite 3

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 with asthma 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 with acute respiratory signs/symptoms (e.g., wheezing) (see section 4.3). ADASUVE has not been investigated in patients with other forms of lung disease. It is recommended to observe patients during the 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 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). 3 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 tre

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HOS-155460 · has-warning-information · PDF-Seite 15

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 with asthma 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 with acute respiratory signs/symptoms (e.g., wheezing) (see section 4.3). ADASUVE has not been investigated in patients with other forms of lung disease. It is recommended to observe patients during the 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 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). 15 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 t

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