Adasuve

Name: Adasuve

Uses of Adasuve

  • It is used to treat schizophrenia.
  • It is used to treat bipolar problems.
  • It may be given to you for other reasons. Talk with the doctor.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Trouble controlling body movements, twitching, change in balance, trouble swallowing or speaking.
  • Shakiness, trouble moving around, or stiffness.
  • Very bad dizziness or passing out.
  • A fast heartbeat.
  • Very bad headache.
  • Feeling confused.
  • Change in eyesight, eye pain, or very bad eye irritation.
  • Seizures.
  • Trouble passing urine.
  • Slurred speech.
  • Feeling very tired or weak.
  • Any unexplained bruising or bleeding.
  • Enlarged breasts.
  • Nipple discharge.
  • Change in sex ability.
  • For women, no period.
  • Restlessness.
  • A very bad and sometimes deadly health problem called neuroleptic malignant syndrome (NMS) may happen. Call your doctor right away if you have any fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, heartbeat that does not feel normal, or are sweating a lot.
  • Some people who take this medicine may get a very bad muscle problem called tardive dyskinesia. This muscle problem may not go away even if Adasuve is stopped. Sometimes, signs may lessen or go away over time after this medicine is stopped. The risk of tardive dyskinesia may be greater in people with diabetes and in older adults, especially older women. The risk is also greater the longer you take Adasuve or with higher doses. Muscle problems may also occur after short-term use with low doses. Call your doctor right away if you have trouble controlling body movements or if you have muscle problems with your tongue, face, mouth, or jaw like tongue sticking out, puffing cheeks, mouth puckering, or chewing.

What are some other side effects of Adasuve?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Feeling sleepy.
  • Trouble sleeping.
  • Dry mouth.
  • Hard stools (constipation).
  • Change in taste.
  • Throat irritation.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Indications and usage

Adasuve 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 [see Clinical Studies (14)].

The efficacy of Adasuve was established in one study of acute agitation in patients with schizophrenia and one study of acute agitation in patients with bipolar I disorder [see Clinical Studies (14)].

Limitations of Use:

As part of the Adasuve REMS Program to mitigate the risk of bronchospasm, Adasuve must be administered only in an enrolled healthcare facility [see Warnings and Precautions (5.2)].

Contraindications

Adasuve is contraindicated in patients with the following:

  • Current diagnosis or history of asthma, COPD, or other lung disease associated with bronchospasm [see Warnings and Precautions (5.1)]
  • Acute respiratory symptoms or signs (e.g., wheezing) [see Warnings and Precautions (5.1)]
  • Current use of medications to treat airways disease, such as asthma or COPD [see Warnings and Precautions (5.1)]
  • History of bronchospasm following Adasuve treatment [see Warnings and Precautions (5.1)]
  • Known hypersensitivity to loxapine or amoxapine. Serious skin reactions have occurred with oral loxapine and amoxapine.

Clinical pharmacology

12.1       Mechanism of Action

The mechanism of action of loxapine in the treatment of agitation associated with schizophrenia is unknown. However, its efficacy could be mediated through a combination of antagonism of central dopamine D2 and serotonin 5-HT2A receptors. The mechanism of action of loxapine in the treatment of agitation associated with bipolar I disorder is unknown. 

12.2       Pharmacodynamics

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 α2 (orthostatic hypotension) receptors (Ki values of 15 nM, 117 nM and 250 nM, respectively).

Thorough QTc Study

Adasuve did not prolong the QTc interval. The effect of Adasuve 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 Adasuve 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 placebo-adjusted, baseline-corrected QTc based on individual correction method was below 10 milliseconds, the threshold for regulatory concern.

12.3       Pharmacokinetics

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

Administration of Adasuve 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 Adasuve 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 Adasuve 10 mg
Parameter Healthy Subjects
Adasuve 10 mg (N=114)
AUC0-2h (ng•h/mL), mean ± SD 66.7 ± 18.2
AUCinf (ng•h/mL), mean ± SD 188 ± 47
Cmax (ng/mL), mean ± SD 257 ± 219
Tmax (minutes), median (25%, 75%) 1.13 (1, 2)
Half-life(h), mean ± SD 7.61 ± 1.87

Figure 8. Mean Plasma Concentrations of Loxapine following Single-Dose Administration Adasuve 10 mg in Healthy Subjects

Distribution: 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.

Metabolism: 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 Adasuve, 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: 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.

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

Special Populations:

Pharmacokinetics in Smokers: Loxapine exposures in nonsmokers and smokers are similar, with geometric mean ratios of 92%, 85%, and 99% for AUC0-2h, AUCinf, and Cmax respectively. No dosage adjustment is recommended based on smoking status.

Demographic Effects: There were no clinically significant differences in loxapine pharmacokinetics following administration of Adasuve in subgroups based on age, weight, body mass index, gender, or race.

Side effects

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

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

Clinical Trials Experience

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 ADASUVE 10 mg in the treatment of patients with acute agitation associated with schizophrenia or bipolar I disorder. In the 3 trials, 259 patients received ADASUVE 10 mg, and 263 received placebo [see Clinical Studies].

Commonly Observed Adverse Reactions

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 ADASUVE 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

Adverse Reaction Placebo
(n = 263)
ADASUVE
(n = 259)
Dysgeusia 5% 14%
Sedation 10% 12%
Throat Irritation 0% 3%

Airway Adverse Reactions In The 3 Trials In Acute Agitation

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 ADASUVE group, compared to the placebo group: 0% (0/263) in the placebo group and 0.8% (2/259) in the ADASUVE 10 mg group. One patient with schizophrenia, without a history of pulmonary disease, had significant bronchospasm requiring rescue treatment with a bronchodilator and oxygen.

Bronchospasm And Airway Adverse Reactions In Pulmonary Safety Trials

Clinical pulmonary safety trials demonstrated that ADASUVE 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 ADASUVE 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 ADASUVE 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 ADASUVE 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 ADASUVE-treated patients and 12% of placebo-treated patients. There were no serious adverse events. Nine of 26 (35%) patients in the ADASUVE 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 ADASUVE 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 ADASUVE 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 ADASUVE group (19%) than in the placebo group (11%). There were no serious adverse events. Seven of 25 (28%) patients in the ADASUVE 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 ADASUVE 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

  Maximum % FEV↓ Healthy Volunteer Asthma COPD
Placebo
n (%)
N=26
ADASUVE 10 mg
n (%)
N=26
Placebo
n (%)
N=26
ADASUVE 10 mg
n (%)
N=26
Placebo
n (%)
N=27
ADASUVE 10 mg
n (%)
N=25
After any Dose ≥ 10 7 (27) 7 (27) 3 (12) 22 (85) 18 (67) 20 (80)
≥ 15 1 (4) 5 (19) 1 (4) 16 (62) 9 (33) 14 (56)
≥ 20 0 1 (4) 1 (4) 11 (42) 3 (11) 10 (40)
After Dose 1   N=26 N=26 N=26 N=26 N=27 N=25
≥ 10 4 (15) 5 (19) 2 (8) 16 (62) 8 (30) 16 (64)
≥ 15 1 (4) 2 (8) 1 (4) 8 (31) 4 (15) 10 (40)
≥ 20 0 0 1 (4) 6 (23) 2 (7) 9 (36)
After Dose 2   N=26 N=25 N=25 N=17 N=26 N=19
≥ 10 5 (19) 6 (24) 3 (12) 12 (71) 15 (58) 12 (63)
≥ 15 0 5 (20) 1 (4) 9 (53) 6 (23) 10 (53)
≥ 20 0 1 (4) 1 (4) 5 (30) 1 (4) 5 (26)

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 ADASUVE in 259 patients with agitation associated with schizophrenia or bipolar disorder, extrapyramidal reactions occurred. One patient (0.4%) treated with ADASUVE developed neck dystonia and oculogyration. The incidence of akathisia was 0% and 0.4% in the placebo and ADASUVE groups, respectively.

Dystonia (Antipsychotic Class Effect): Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during treatment with ADASUVE. 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 ADASUVE. 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.

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