Adasuve

Overdose

As would be expected from the pharmacologic actions of loxapine, the clinical findings may include CNS depression, unconsciousness, profound hypotension, respiratory depression, extrapyramidal symptoms, and seizure.

For the most up to date information on the management of %medicine_name% overdosage, contact a certified poison control center (1-800-222-1222 or www.poison.org). Provide supportive care including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.

Contraindications

%medicine_name% is contraindicated in patients with the following:

• Current diagnosis or history of asthma, COPD, or other lung disease associated with bronchospasm
• Acute respiratory symptoms or signs (e.g., wheezing)
• Current use of medications to treat airways disease, such as asthma or COPD
• History of bronchospasm following %medicine_name% treatment

Known hypersensitivity to loxapine or amoxapine. Serious skin reactions have occurred with oral loxapine and amoxapine.

Undesirable effects

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Hypersensitivity (serious skin reactions)
• Bronchospasm
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
• Neuroleptic Malignant Syndrome
• Hypotension and syncope
• Seizure
• Potential for Cognitive and Motor Impairment
• Cerebrovascular Reactions, Including Stroke, in Elderly Patients with Dementia- Related Psychosis
• Anticholinergic Reactions Including Exacerbation of Glaucoma and Urinary Retention

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The following findings are based on pooled data from three short-term (24-hour), randomized, double-blind, placebo-controlled clinical trials (Studies 1, 2, and 3) of %medicine_name% 10 mg in the treatment of patients with acute agitation associated with schizophrenia or bipolar I disorder. In the 3 trials, 259 patients received %medicine_name% 10 mg, and 263 received placebo.

In the 3 trials in acute agitation, the most common adverse reactions were dysgeusia, sedation, and throat irritation. These reactions occurred at a rate of at least 2% of the %medicine_name% group and at a rate greater than in the placebo group. (Refer to Table 1).

Table 1: Adverse Reactions in 3 Pooled Short-Term, Placebo-Controlled Trials (Studies 1, 2, and 3) in Patients with Schizophrenia or Bipolar Disorder

Agitated patients with Schizophrenia or Bipolar Disorder: In the 3 short-term (24-hour), placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar disorder (Studies 1, 2, and 3), bronchospasm (which includes reports of wheezing, shortness of breath and cough) occurred more frequently in the %medicine_name% group, compared to the placebo group: 0% (0/263) in the placebo group and 0.8% (2/259) in the %medicine_name% 10 mg group. One patient with schizophrenia, without a history of pulmonary disease, had significant bronchospasm requiring rescue treatment with a bronchodilator and oxygen.

Clinical pulmonary safety trials demonstrated that %medicine_name% can cause bronchospasm as measured by FEV1, and as indicated by respiratory signs and symptoms in the trials. In addition, the trials demonstrated that patients with asthma or other pulmonary diseases, such as COPD are at increased risk of bronchospasm. The effect of %medicine_name% on pulmonary function was evaluated in 3 randomized, double-blind, placebo-controlled clinical pulmonary safety trials in healthy volunteers, patients with asthma, and patients with COPD. Pulmonary function was assessed by serial FEV1 tests, and respiratory signs and symptoms were assessed. In the asthma and COPD trials, patients with respiratory symptoms or FEV1 decrease of ≥ 20% were administered rescue treatment with albuterol (metered dose inhaler or nebulizer) as required. These patients were not eligible for a second dose; however, they had continued FEV1 monitoring in the trial.

Healthy Volunteers: In the healthy volunteer crossover trial, 30 subjects received 2 doses of either %medicine_name% or placebo 8 hours apart, and 2 doses of the alternate treatment at least 4 days later. The results for maximum decrease in FEV1 are presented in Table 2. No subjects in this trial developed airway related adverse reactions (cough, wheezing, chest tightness, or dyspnea).

Asthma Patients: In the asthma trial, 52 patients with mild-moderate persistent asthma (with FEV1 ≥ 60% of predicted) were randomized to treatment with 2 doses of %medicine_name% 10 mg or placebo. The second dose was to be administered 10 hours after the first dose. Approximately 67% of these patients had a baseline FEV1 ≥ 80% of predicted. The remaining patients had an FEV1 60-80% of predicted. Nine patients (17%) were former smokers. As shown in Table 2 and Figure 7, there was a marked decrease in FEV1 immediately following the first dose (maximum mean decreases in FEV1 and % predicted FEV1 were 303 mL and 9.1%, respectively). Furthermore, the effect on FEV1 was greater following the second dose (maximum mean decreases in FEV1 and % predicted FEV1 were 537 mL and 14.7 %, respectively). Respiratory-related adverse reactions (bronchospasm, chest discomfort, cough, dyspnea, throat tightness, and wheezing) occurred in 54% of %medicine_name%-treated patients and 12% of placebo-treated patients. There were no serious adverse events. Nine of 26 (35%) patients in the %medicine_name% group, compared to one of 26 (4%) in the placebo group, did not receive a second dose of study medication, because they had a ≥ 20% decrease in FEV1 or they developed respiratory symptoms after the first dose. Rescue medication (albuterol via metered dose inhaler or nebulizer) was administered to 54% of patients in the %medicine_name% group [7 patients (27%) after the first dose and 7 of the remaining 17 patients (41%) after the second dose] and 12% in the placebo group (1 patient after the first dose and 2 patients after the second dose).

COPD Patients: In the COPD trial, 53 patients with mild to severe COPD (with FEV1 ≥ 40% of predicted) were randomized to treatment with 2 doses of %medicine_name% 10 mg or placebo. The second dose was to be administered 10 hours after the first dose. Approximately 57% of these patients had moderate COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II]; 32% had severe disease (GOLD Stage III); and 11% had mild disease (GOLD Stage I). As illustrated in Table 2 there was a decrease in FEV1 soon after the first dose (maximum mean decreases in FEV1 and % predicted FEV1 were 96 mL and 3.5%, respectively), and the effect on FEV1 was greater following the second dose (maximum mean decreases in FEV1 and % predicted FEV1 were 125 mL and 4.5%, respectively). Respiratory adverse reactions occurred more frequently in the %medicine_name% group (19%) than in the placebo group (11%). There were no serious adverse events. Seven of 25 (28%) patients in the %medicine_name% group and 1of 27 (4%) in the placebo group did not receive a second dose of study medication because of a ≥ 20% decrease in FEV1 or the development of respiratory symptoms after the first dose. Rescue medication (albuterol via MDI or nebulizer) was administered to 23% of patients in the %medicine_name% group: 8% of patients after the first dose and 21% of patients after the second dose, and to 15% of patients in the placebo group.

Table 2: Maximum Decrease in FEV1 from Baseline in the Healthy Volunteer, Asthma, and COPD Trials

FEV1 categories are cumulative; i.e. a subject with a maximum decrease of 21% is included in all 3 categories. Patients with a ≥ 20% decrease in FEV1 did not receive a second dose of study drug.

Figure 7: LS Mean Change from Baseline in FEV1 in Patients with Asthma

Patients with a ≥ 20% decrease in FEV1 did not receive a second dose of study drug and are not included in the curves beyond hour 10.

Extrapyramidal Symptoms (EPS): Extrapyramidal reactions have occurred during the administration of oral loxapine. In most patients, these reactions involved parkinsonian symptoms such as tremor, rigidity, and masked facies. Akathisia (motor restlessness) has also occurred.

In the 3 short-term (24-hour), placebo-controlled trials of %medicine_name% in 259 patients with agitation associated with schizophrenia or bipolar disorder, extrapyramidal reactions occurred. One patient (0.4%) treated with %medicine_name% developed neck dystonia and oculogyration. The incidence of akathisia was 0% and 0.4% in the placebo and %medicine_name% groups, respectively.

Dystonia (Antipsychotic Class Effect): Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during treatment with %medicine_name%. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, difficulty swallowing or breathing, and/or protrusion of the tongue.

Acute dystonia tends to be dose-related, but can occur at low doses, and occurs more frequently with first generation antipsychotic drugs such as %medicine_name%. The risk is greater in males and younger age groups.

Cardiovascular Reactions: Tachycardia, hypotension, hypertension, orthostatic hypotension, lightheadedness, and syncope have been reported with oral administration of loxapine.

Therapeutic indications

%medicine_name% is a typical antipsychotic indicated for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.

“Psychomotor agitation” is defined in DSM-IV as “excessive motor activity associated with a feeling of inner tension.” Patients experiencing agitation often manifest behaviors that interfere with their care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior), leading clinicians to the use of rapidly absorbed antipsychotic medications to achieve immediate control of the agitation.

The efficacy of %medicine_name% was established in one study of acute agitation in patients with schizophrenia and one study of acute agitation in patients with bipolar I disorder.

As part of the %medicine_name% REMS Program to mitigate the risk of bronchospasm, %medicine_name% must be administered only in an enrolled healthcare facility.

Pharmacodynamic properties

Loxapine acts as an antagonist at central serotonin and dopamine receptors, with high affinity for serotonin 5-HT2A and dopamine D1, D2, D3, and D4 receptors (Ki values of 2 nM, 18 nM, 10 nM, 21 nM, 9 nM, respectively). Some of the adverse effects of loxapine may be related to the antagonism of histamine H1 (somnolence), muscarinic M1 (anticholinergic), and adrenergic a2 (orthostatic hypotension) receptors (Ki values of 15 nM, 117 nM and 250 nM, respectively).

%medicine_name% did not prolong the QTc interval. The effect of %medicine_name% on QTc prolongation was evaluated in a randomized, double-blinded, positive- (moxifloxacin 400 mg) and placebo-controlled parallel study in healthy subjects. A total of 48 healthy subjects were administered %medicine_name% 10 mg. In this study with a demonstrated ability to detect small effects, the upper bound of the 90% confidence interval (CI) for the largest placeboadjusted, baseline-corrected QTc based on individual correction method was below 10 milliseconds, the threshold for regulatory concern.

Pharmacokinetic properties

The single-dose pharmacokinetic parameters of loxapine following administration of single doses of %medicine_name% 10 mg in healthy adult subjects are presented in Table 3 and Figure 8.

Administration of %medicine_name% resulted in rapid absorption of loxapine, with a median time of maximum plasma concentration (Tmax) of 2 minutes. Loxapine exposure in the first 2 hours after administration (AUC0-2h) was 66.7 ng•h/mL for the 10 mg dose. As a consequence of the very rapid absorption of loxapine after oral inhalation, there is substantial variability in the early plasma concentrations of loxapine. The mean plasma loxapine concentrations following administration of %medicine_name% were linear over the clinical dose range. AUC0-2h, AUCinf, and Cmax increased in a dose-dependent manner.

Table 3: Pharmacokinetics in Healthy Adult Subjects Administered a Single Dose of %medicine_name% 10 mg

Figure 8: Mean Plasma Concentrations of Loxapine following Single-Dose Administration %medicine_name% 10 mg in Healthy Subjects

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 metabolized extensively in the liver following oral administration, with multiple metabolites formed. The main metabolic pathways include: 1) hydroxylation to form 8-OH-loxapine by CYP1A2 and 7-OH-loxapine by CYP3A4 and CYP2D6, 2) N-oxidation to form loxapine N-oxide by flavanoid monoamine oxidases (FMOs), and 3) de-methylation to form amoxapine. Because there are multiple metabolic pathways, the risk of metabolic interactions caused by an effect on an individual isoform is minimal. For %medicine_name%, the order of metabolites observed in humans (based on systemic exposure) was 8-OH-loxapine > > loxapine N-oxide, 7-OH-loxapine > amoxapine. Plasma levels of 8-OH-loxapine are similar to those of the parent compound.

Excretion occurs mainly in the first 24 hours. Metabolites are excreted in the urine in the form of conjugates and in the feces unconjugated. The terminal elimination half-life (T½) ranged from 6 to 8 hours.

In vitro studies indicated that loxapine was not a substrate for p-glycoprotein (P-gp): however, loxapine inhibited P-gp.

Date of revision of the text

Fertility, pregnancy and lactation

Pregnancy Category C

There are no adequate and well-controlled studies of %medicine_name% use in pregnant women. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Loxapine, the active ingredient in %medicine_name%, has demonstrated increased embryofetal toxicity and death in rat fetuses and offspring exposed to doses approximately 0.5-fold the maximum recommended human dose (MRHD) on a mg/m² basis. %medicine_name% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorders in these neonates. These complications have varied in severity; in some cases symptoms have been self-limited, but in other cases neonates have required intensive care unit support and prolonged hospitalization.

In rats, embryofetal toxicity (increased fetal resorptions, reduced weights, and hydronephrosis with hydroureter) was observed following oral administration of loxapine during the period of organogenesis at a dose of 1 mg/kg/day. This dose is equivalent to the MRHD of 10 mg/day on a mg/m² basis. In addition, fetal toxicity (increased prenatal death, decreased postnatal survival, reduced fetal weights, delayed ossification, and/or distended renal pelvis with reduced or absent papillae) was observed following oral administration of loxapine from mid-pregnancy through weaning at doses of 0.6 mg/kg and higher. This dose is approximately half the MRHD of 10 mg/day on a mg/m² basis.

No teratogenicity was observed following oral administration of loxapine during the period of organogenesis in the rat, rabbit, or dog at doses up to 12, 60, and 10 mg/kg, respectively. These doses are approximately 12-, 120-, and 32-fold the MRHD of 10 mg/day on a mg/m² basis, respectively.

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

%medicine_name% can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest. Administer %medicine_name% only in an enrolled healthcare facility that has immediate access on-site to equipment and personnel trained to manage acute bronchospasm, including advanced airway management (intubation and mechanical ventilation). Prior to administering %medicine_name%, screen patients regarding a current diagnosis or history of asthma, COPD, and other lung disease associated with bronchospasm, acute respiratory symptoms or signs, current use of medications to treat airways disease, such as asthma or COPD; and examine patients (including chest auscultation) for respiratory abnormalities (e.g., wheezing). Monitor patients for symptoms and signs of bronchospasm (i.e., vital signs and chest auscultation) at least every 15 minutes for a minimum of one hour following treatment with %medicine_name%. %medicine_name% can cause sedation, which can mask the symptoms of bronchospasm.

Because clinical trials in patients with asthma or COPD demonstrated that the degree of bronchospasm, as indicated by changes in forced expiratory volume in 1 second (FEV1), was greater following a second dose of %medicine_name%, limit %medicine_name% use to a single dose within a 24 hour period.

Advise all patients of the risk of bronchospasm. Advise them to inform the healthcare professional if they develop any breathing problems such as wheezing, shortness of breath, chest tightness, or cough following treatment with %medicine_name%.

Because of the risk of bronchospasm, %medicine_name% is available only through a restricted program under a REMS called the %medicine_name% REMS. Required components of the %medicine_name% REMS are:

• Healthcare facilities that dispense and administer %medicine_name% must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site access to equipment and personnel trained to provide advance airway management, including intubation and mechanical ventilation.
• Wholesalers and distributors that distribute %medicine_name% must enroll in the program and distribute only to enrolled healthcare facilities.

Further information is available at www.%medicine_name%rems.com or 1-855-755-0492.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the cases of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies can be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. %medicine_name% is not approved for the treatment of elderly patients with dementia-related psychosis.

Antipsychotic drugs can cause a potentially fatal symptom complex termed Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Associated features can include elevated serum creatine phosphokinase (CPK) concentration, rhabdomyolysis, elevated serum and urine myoglobin concentration, and renal failure. NMS did not occur in the %medicine_name% clinical program.

The diagnostic evaluation of patients with this syndrome is complicated. It is important to consider the presence of other serious medical conditions (e.g., pneumonia, systemic infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, or drug fever).

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs that may contribute to the underlying disorder, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

%medicine_name% can cause hypotension, orthostatic hypotension, and syncope. Use %medicine_name% with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (dehydration, hypovolemia, or treatment with antihypertensive medications or other drugs that affect blood pressure or reduce heart rate).

In the presence of severe hypotension requiring vasopressor therapy, the preferred drugs may be norepinephrine or phenylephrine. Epinephrine should not be used, because beta stimulation may worsen hypotension in the setting of %medicine_name%-induced partial alpha blockade.

In short-term (24-hour) placebo-controlled trials of patients with agitation associated with schizophrenia or bipolar I disorder, hypotension occurred in 0.4% and 0.8% in the %medicine_name% 10 mg and placebo groups, respectively. There were no cases of orthostatic hypotension, postural symptoms, presyncope or syncope. A systolic blood pressure ≤ 90 mm Hg with a decrease of ≥ 20 mm Hg occurred in 1.5% and 0.8% of the %medicine_name% 10 mg and placebo groups, respectively. A diastolic blood pressure ≤ 50 mm Hg with a decrease of ≥ 15 mmHg occurred in 0.8% and 0.4% of the %medicine_name% 10 mg and placebo groups, respectively.

In 5 Phase 1 studies in normal volunteers, the incidence of hypotension was 3% and 0% in %medicine_name% 10 mg and the placebo groups, respectively. The incidence of syncope or presyncope in normal volunteers was 2.3% and 0% in the %medicine_name% and placebo groups, respectively. In normal volunteers, a systolic blood pressure ≤ 90 mm Hg with a decrease of ≥ 20 mm Hg occurred in 5.3% and 1.1% in the %medicine_name% and placebo groups, respectively. A diastolic blood pressure ≤ 50 mm Hg with a decrease of ≥ 15 mm Hg occurred in 7.5% and 3.3% in the %medicine_name% and placebo groups, respectively.

%medicine_name% lowers the seizure threshold. Seizures have occurred in patients treated with oral loxapine. Seizures can occur in epileptic patients even during antiepileptic drug maintenance therapy. In short term (24 hour), placebo-controlled trials of %medicine_name%, there were no reports of seizures.

%medicine_name% can impair judgment, thinking, and motor skills. In short-term, placebocontrolled trials, sedation and/or somnolence were reported in 12% and 10% in the %medicine_name% and placebo groups, respectively. No patients discontinued treatment because of sedation or somnolence.

The potential for cognitive and motor impairment is increased when %medicine_name% is administered concurrently with other CNS depressants. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with %medicine_name% does not affect them adversely.

In placebo-controlled trials with atypical antipsychotics in elderly patients with dementia- related psychosis, there was a higher incidence of cerebrovascular adverse reactions (stroke and transient ischemic attacks), including fatalities, compared to placebo-treated patients. %medicine_name% is not approved for the treatment of patients with dementia-related psychosis.

%medicine_name% has anticholinergic activity, and it has the potential to cause anticholinergic adverse reactions including exacerbation of glaucoma or urinary retention. The concomitant use of other anticholinergic drugs (e.g., antiparkinson drugs) with %medicine_name% could have additive effects.

See FDA-approved patient labeling (Medication Guide)

Advise patients and caregivers that there is a risk of bronchospasm. Advise patients to inform their healthcare professional if they develop any breathing problems such as wheezing, shortness of breath, chest tightness, or cough following treatment with %medicine_name%

Caution patients and caregivers about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that %medicine_name% has not affected them adversely.

Caution patients and caregivers about the potential for sedation, especially when used concurrently with other CNS depressants (e.g., alcohol, opioid analgesics, benzodiazepines, tricyclic antidepressants, general anesthetics, phenothiazines, sedative/hypnotics, muscle relaxants, and/or illicit CNS depressants).

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).

Advise patients and caregivers of the risk of hypotension or orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing).

Counsel patients and caregivers about the potential risks of anticholinergic reactions, such as exacerbation of glaucoma and urinary retention.

Counsel patients and caregivers regarding the potential risk to the fetus or neonate.

Counsel patients and caregivers regarding the potential risk to the infant.

No adequate studies have been conducted.

Loxapine did not cause mutation or chromosomal aberration when tested in vitro and in vivo. Loxapine was negative in the Ames gene mutation assay, the human peripheral blood lymphocyte chromosomal aberration assay, and in the in vivo mouse bone marrow micronucleus assay up to 40 mg/kg (20-fold the MRHD on mg/m² basis). Loxapine metabolite 8-OH-loxapine was not mutagenic in the in vitro Ames reverse mutation assay and was not clastogenic in the in vitro human peripheral blood lymphocyte chromosomal aberration assay.

Loxapine had no effects on fertility or early embryonic development in male rats or in male and female rabbits following oral administration. Mating was decreased in female rats because these animals were in persistent diestrus, an expected pharmacologic effect for this class of compounds. This occurred at doses approximately 0.2- and 1-fold the MRHD of 10 mg/day on a mg/m² basis.

In general, no dose adjustment for %medicine_name% is required on the basis of a patient's age, gender, race, smoking status, hepatic function, or renal function.

Pregnancy Category C

There are no adequate and well-controlled studies of %medicine_name% use in pregnant women. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Loxapine, the active ingredient in %medicine_name%, has demonstrated increased embryofetal toxicity and death in rat fetuses and offspring exposed to doses approximately 0.5-fold the maximum recommended human dose (MRHD) on a mg/m² basis. %medicine_name% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorders in these neonates. These complications have varied in severity; in some cases symptoms have been self-limited, but in other cases neonates have required intensive care unit support and prolonged hospitalization.

In rats, embryofetal toxicity (increased fetal resorptions, reduced weights, and hydronephrosis with hydroureter) was observed following oral administration of loxapine during the period of organogenesis at a dose of 1 mg/kg/day. This dose is equivalent to the MRHD of 10 mg/day on a mg/m² basis. In addition, fetal toxicity (increased prenatal death, decreased postnatal survival, reduced fetal weights, delayed ossification, and/or distended renal pelvis with reduced or absent papillae) was observed following oral administration of loxapine from mid-pregnancy through weaning at doses of 0.6 mg/kg and higher. This dose is approximately half the MRHD of 10 mg/day on a mg/m² basis.

No teratogenicity was observed following oral administration of loxapine during the period of organogenesis in the rat, rabbit, or dog at doses up to 12, 60, and 10 mg/kg, respectively. These doses are approximately 12-, 120-, and 32-fold the MRHD of 10 mg/day on a mg/m² basis, respectively.

It is not known whether %medicine_name% is present in human milk. Loxapine and its metabolites are present in the milk of lactating dogs. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from %medicine_name%, a decision should be made whether to discontinue nursing or discontinue %medicine_name%, taking into account the importance of the drug to the mother.

The safety and effectiveness of %medicine_name% in pediatric patients have not been established.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. %medicine_name% is not approved for the treatment of dementia-related psychosis. Placebocontrolled studies of %medicine_name% in patients with agitation associated with schizophrenia or bipolar disorder did not include patients over 65 years of age.

Dosage (Posology) and method of administration

%medicine_name% must be administered only by a healthcare professional. %medicine_name% is administered by oral inhalation only. The recommended dose for acute agitation is 10 mg administered by oral inhalation, using a single-use inhaler. Administer only a single dose within a 24-hour period.

Prior to administering %medicine_name%, screen all patients for a history of asthma, COPD, or other pulmonary disease, and examine patients (including chest auscultation) for respiratory signs (e.g. wheezing).

Read all of these instructions prior to administering %medicine_name%.

Step 1. Open the Pouch

When ready to use, tear open the foil pouch and remove the inhaler from the package (see Figure 1).

Figure 1: Tearing the pouch

When the %medicine_name% inhaler is removed from the pouch, the indicator light is off (see Figure 2).

Figure 2: %medicine_name% Inhaler with Indicator Light

Step 2. Pull Tab

Firmly pull the plastic tab from the rear of the inhaler (see Figure 3). Check that the green light turns on. This indicates that the inhaler is ready for use. Use the inhaler within 15 minutes after removing the tab to prevent automatic deactivation of the inhaler. The green light will turn off, indicating that the inhaler is not usable. Discard the inhaler after one use.

Figure 3

Step 3. Explain Procedures to the Patient

Explain the administration procedures to the patient prior to use, and advise the patient that it is important to follow the instructions. Inform the patient that the inhaler may produce a flash of light and a clicking sound, and it may become warm during use. These are normal.

Step 4. Instruct the Patient to Exhale

Instruct the patient to hold the inhaler away from the mouth and breathe out fully to empty the lungs (see Figure 4).

Figure 4: Exhale

Step 5. Instruct the Patient to Inhale

Instruct the patient to put the mouthpiece of the inhaler between the lips, close the lips, and inhale through the mouthpiece with a steady deep breath (see Figure 5). Check that the green light turns off indicating that the dose has been delivered.

Figure 5: Inhale

Step 6. Instruct the Patient to Hold Breath

Instruct the patient to remove the mouthpiece from the mouth and hold the breath for as long as possible, up to 10 seconds (see Figure 6).

Figure 6: Hold Breath

Important: If the green light remains on after the patient inhales, the dose of %medicine_name% has NOT been delivered. Instruct the patient to repeat Step 4, Step 5, and Step 6 up to 2 additional times. If the green light still does not turn off, discard the inhaler and use a new one.

Monitor the patient for signs and symptoms of bronchospasm after %medicine_name% administration. Perform a physical examination, including chest auscultation, at least every 15 minutes for at least one hour after %medicine_name% administration.

Interaction with other medicinal products and other forms of interaction

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Hypersensitivity (serious skin reactions)
• Bronchospasm
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
• Neuroleptic Malignant Syndrome
• Hypotension and syncope
• Seizure
• Potential for Cognitive and Motor Impairment
• Cerebrovascular Reactions, Including Stroke, in Elderly Patients with Dementia- Related Psychosis
• Anticholinergic Reactions Including Exacerbation of Glaucoma and Urinary Retention

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The following findings are based on pooled data from three short-term (24-hour), randomized, double-blind, placebo-controlled clinical trials (Studies 1, 2, and 3) of %medicine_name% 10 mg in the treatment of patients with acute agitation associated with schizophrenia or bipolar I disorder. In the 3 trials, 259 patients received %medicine_name% 10 mg, and 263 received placebo.

In the 3 trials in acute agitation, the most common adverse reactions were dysgeusia, sedation, and throat irritation. These reactions occurred at a rate of at least 2% of the %medicine_name% group and at a rate greater than in the placebo group. (Refer to Table 1).

Table 1: Adverse Reactions in 3 Pooled Short-Term, Placebo-Controlled Trials (Studies 1, 2, and 3) in Patients with Schizophrenia or Bipolar Disorder

Agitated patients with Schizophrenia or Bipolar Disorder: In the 3 short-term (24-hour), placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar disorder (Studies 1, 2, and 3), bronchospasm (which includes reports of wheezing, shortness of breath and cough) occurred more frequently in the %medicine_name% group, compared to the placebo group: 0% (0/263) in the placebo group and 0.8% (2/259) in the %medicine_name% 10 mg group. One patient with schizophrenia, without a history of pulmonary disease, had significant bronchospasm requiring rescue treatment with a bronchodilator and oxygen.

Clinical pulmonary safety trials demonstrated that %medicine_name% can cause bronchospasm as measured by FEV1, and as indicated by respiratory signs and symptoms in the trials. In addition, the trials demonstrated that patients with asthma or other pulmonary diseases, such as COPD are at increased risk of bronchospasm. The effect of %medicine_name% on pulmonary function was evaluated in 3 randomized, double-blind, placebo-controlled clinical pulmonary safety trials in healthy volunteers, patients with asthma, and patients with COPD. Pulmonary function was assessed by serial FEV1 tests, and respiratory signs and symptoms were assessed. In the asthma and COPD trials, patients with respiratory symptoms or FEV1 decrease of ≥ 20% were administered rescue treatment with albuterol (metered dose inhaler or nebulizer) as required. These patients were not eligible for a second dose; however, they had continued FEV1 monitoring in the trial.

Healthy Volunteers: In the healthy volunteer crossover trial, 30 subjects received 2 doses of either %medicine_name% or placebo 8 hours apart, and 2 doses of the alternate treatment at least 4 days later. The results for maximum decrease in FEV1 are presented in Table 2. No subjects in this trial developed airway related adverse reactions (cough, wheezing, chest tightness, or dyspnea).

Asthma Patients: In the asthma trial, 52 patients with mild-moderate persistent asthma (with FEV1 ≥ 60% of predicted) were randomized to treatment with 2 doses of %medicine_name% 10 mg or placebo. The second dose was to be administered 10 hours after the first dose. Approximately 67% of these patients had a baseline FEV1 ≥ 80% of predicted. The remaining patients had an FEV1 60-80% of predicted. Nine patients (17%) were former smokers. As shown in Table 2 and Figure 7, there was a marked decrease in FEV1 immediately following the first dose (maximum mean decreases in FEV1 and % predicted FEV1 were 303 mL and 9.1%, respectively). Furthermore, the effect on FEV1 was greater following the second dose (maximum mean decreases in FEV1 and % predicted FEV1 were 537 mL and 14.7 %, respectively). Respiratory-related adverse reactions (bronchospasm, chest discomfort, cough, dyspnea, throat tightness, and wheezing) occurred in 54% of %medicine_name%-treated patients and 12% of placebo-treated patients. There were no serious adverse events. Nine of 26 (35%) patients in the %medicine_name% group, compared to one of 26 (4%) in the placebo group, did not receive a second dose of study medication, because they had a ≥ 20% decrease in FEV1 or they developed respiratory symptoms after the first dose. Rescue medication (albuterol via metered dose inhaler or nebulizer) was administered to 54% of patients in the %medicine_name% group [7 patients (27%) after the first dose and 7 of the remaining 17 patients (41%) after the second dose] and 12% in the placebo group (1 patient after the first dose and 2 patients after the second dose).

COPD Patients: In the COPD trial, 53 patients with mild to severe COPD (with FEV1 ≥ 40% of predicted) were randomized to treatment with 2 doses of %medicine_name% 10 mg or placebo. The second dose was to be administered 10 hours after the first dose. Approximately 57% of these patients had moderate COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II]; 32% had severe disease (GOLD Stage III); and 11% had mild disease (GOLD Stage I). As illustrated in Table 2 there was a decrease in FEV1 soon after the first dose (maximum mean decreases in FEV1 and % predicted FEV1 were 96 mL and 3.5%, respectively), and the effect on FEV1 was greater following the second dose (maximum mean decreases in FEV1 and % predicted FEV1 were 125 mL and 4.5%, respectively). Respiratory adverse reactions occurred more frequently in the %medicine_name% group (19%) than in the placebo group (11%). There were no serious adverse events. Seven of 25 (28%) patients in the %medicine_name% group and 1of 27 (4%) in the placebo group did not receive a second dose of study medication because of a ≥ 20% decrease in FEV1 or the development of respiratory symptoms after the first dose. Rescue medication (albuterol via MDI or nebulizer) was administered to 23% of patients in the %medicine_name% group: 8% of patients after the first dose and 21% of patients after the second dose, and to 15% of patients in the placebo group.

Table 2: Maximum Decrease in FEV1 from Baseline in the Healthy Volunteer, Asthma, and COPD Trials

FEV1 categories are cumulative; i.e. a subject with a maximum decrease of 21% is included in all 3 categories. Patients with a ≥ 20% decrease in FEV1 did not receive a second dose of study drug.

Figure 7: LS Mean Change from Baseline in FEV1 in Patients with Asthma

Patients with a ≥ 20% decrease in FEV1 did not receive a second dose of study drug and are not included in the curves beyond hour 10.

Extrapyramidal Symptoms (EPS): Extrapyramidal reactions have occurred during the administration of oral loxapine. In most patients, these reactions involved parkinsonian symptoms such as tremor, rigidity, and masked facies. Akathisia (motor restlessness) has also occurred.

In the 3 short-term (24-hour), placebo-controlled trials of %medicine_name% in 259 patients with agitation associated with schizophrenia or bipolar disorder, extrapyramidal reactions occurred. One patient (0.4%) treated with %medicine_name% developed neck dystonia and oculogyration. The incidence of akathisia was 0% and 0.4% in the placebo and %medicine_name% groups, respectively.

Dystonia (Antipsychotic Class Effect): Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during treatment with %medicine_name%. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, difficulty swallowing or breathing, and/or protrusion of the tongue.

Acute dystonia tends to be dose-related, but can occur at low doses, and occurs more frequently with first generation antipsychotic drugs such as %medicine_name%. The risk is greater in males and younger age groups.

Cardiovascular Reactions: Tachycardia, hypotension, hypertension, orthostatic hypotension, lightheadedness, and syncope have been reported with oral administration of loxapine.

%medicine_name% is a central nervous system (CNS) depressant. The concurrent use of %medicine_name% with other CNS depressants (e.g., alcohol, opioid analgesics, benzodiazepines, tricyclic antidepressants, general anesthetics, phenothiazines, sedative/hypnotics, muscle relaxants, and/or illicit CNS depressants) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with %medicine_name%.

%medicine_name% has anticholinergic activity. The concomitant use of %medicine_name% and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma and urinary retention.