Adasuve

Dosage Forms And Strengths

ADASUVE is an inhalation powder supplied in a single-use, disposable inhaler containing 10 mg of loxapine base.

ADASUVE® (loxapine) inhalation powder is supplied as:

ADASUVE 10 mg (NDC 57844-510-11) is a single-use, disposable inhaler containing 10 mg of loxapine, provided in a sealed foil pouch. ADASUVE, 10 mg is supplied in a carton of 5 units per carton (NDC 57844-510-55).

Restricted Access

ADASUVE is only available through a restricted program called the ADASUVE REMS Program [see WARNINGS AND PRECAUTIONS].

Storage And Handling

Store ADASUVE at room temperature, 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Keep out of reach of children.

Keep ADASUVE in pouch until time of use.

ADASUVE contains a lithium battery. Dispose of ADASUVE in accordance with all federal, state and local laws.

Manufactured by: Alexza Pharmaceuticals, Inc., Mountain View, CA 94043. Manufactured for: Teva Select Brands, Horsham, PA 19044, Division of Teva Pharmaceuticals USA, Inc. Revised: Dec 2013

ADASUVE®
(AD-uh-soov)
(loxapine) Inhalation Powder

Read this Medication Guide before you start taking ADASUVE and each time it is given to you. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. You should share this information with your family members and caregivers.

What is the most important information I should know about ADASUVE?

ADASUVE is available only through the ADASUVE Risk Evaluation and Mitigation Strategy (REMS) Program. The healthcare facility must be enrolled in the ADASUVE REMS Program before you can be given ADASUVE.

ADASUVE may cause serious side effects, including:

• Narrowing of the airways (bronchospasm) that can cause you to have problems breathing or to stop breathing. People who have asthma or other airway or lung problems, such as chronic obstructive pulmonary disease (COPD), have a higher risk of bronchospasm when taking ADASUVE. Symptoms of bronchospasm may include:
  • wheezing
  • coughing
  • chest tightness
  • shortness of breath
    Tell your healthcare provider right away if you have any of these symptoms of bronchospasm after taking ADASUVE.
    Your healthcare provider should check you for breathing problems before and after you take ADASUVE.
• Increased risk of death in elderly patients with dementia-related psychosis. Medicines like ADASUVE can raise the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). ADASUVE is not approved for the treatment of patients with dementia-related psychosis.

What is ADASUVE?

ADASUVE is a prescription medicine that is inhaled through your mouth and is used to treat acute agitation in adults with schizophrenia or bipolar I disorder.

It is not known if ADASUVE is safe and effective in children.

Who should not take ADASUVE?

Do not take ADASUVE if you:

• have or have had asthma, chronic obstructive pulmonary disease (COPD), or other airway or lung problems that can cause bronchospasm
• are having problems with wheezing, coughing, chest tightness, or shortness of breath
• are taking medicines to treat asthma or COPD
• have taken ADASUVE before and had bronchospasm
• are allergic to loxapine or amoxapine

What should I tell my healthcare provider before taking ADASUVE?

Before you take ADASUVE, tell your healthcare provider if you:

• have high or low blood pressure
• have or have had heart problems or stroke
• have or have had seizures (convulsions)
• drink alcohol or use street drugs
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if ADASUVE will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if ADASUVE passes into your breast milk. You and your healthcare provider should decide if you will take ADASUVE if you are breastfeeding.

Tell your doctor about all medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

• ADASUVE and other medicines may affect each other causing side effects. ADASUVE may affect the way other medicines work, and other medicines may affect the way ADASUVE works.

Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.

Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

How should I take ADASUVE?

• Your healthcare provider will show you how to take ADASUVE right before you take it.
• Take ADASUVE exactly as your healthcare provider shows you to take it.
• ADASUVE is for oral inhalation only.

What should I avoid while taking ADASUVE?

• Do not drive, operate heavy machinery, or do other dangerous activities until you know how ADASUVE affects you.
• Do not drink alcohol while taking ADASUVE. It can increase your chances of getting serious side effects.

What are the possible side effects of ADASUVE?

ADASUVE can cause serious side effects, including:

• See “What is the most important information I should know about ADASUVE?”
• neuroleptic malignant syndrome (NMS). NMS is a rare but serious condition that may cause death. Symptoms of NMS may include:
  • high fever
  • stiff muscles
  • confusion
  • sweating
  • changes in pulse, heart rate, and blood pressure
    Tell your healthcare provider right away if you have any of these symptoms of NMS after taking ADASUVE.
• low blood pressure (hypotension), lightheadedness, or fainting
• seizures (convulsions)
• severe sleepiness and difficulty with potentially dangerous activities such as driving
• worsening of glaucoma
• difficulty urinating

The most common side effects of ADASUVE include:

• bad, bitter, or metallic taste in your mouth (dysgeusia)
• sleepiness (especially when used with other drugs that cause sleepiness)
• sore throat

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of ADASUVE. For more information ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of ADASUVE.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

This Medication Guide summarizes the most important information about ADASUVE. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about ADASUVE that is written for health professionals.

For more information, go to www.ADASUVE.com or call 1-888-483-8279.

What are the ingredients in ADASUVE?

Active Ingredient: loxapine

Inactive Ingredients: none

This Medication Guide has been approved by the U.S. Food and Drug Administration.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of inhaled loxapine in the pediatric population. Safety and efficacy have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of inhaled loxapine have not been performed in the geriatric population, geriatric-specific problems are not expected to limit the usefulness of inhaled loxapine in the elderly. However, this medicine should not be used for behavioral problems in older adults with dementia.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Bromopride
• Metoclopramide

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Bromazepam
• Buprenorphine
• Bupropion
• Butorphanol
• Carbamazepine
• Codeine
• Dihydrocodeine
• Donepezil
• Doxylamine
• Fentanyl
• Flibanserin
• Hydrocodone
• Hydromorphone
• Levorphanol
• Lithium
• Meperidine
• Methadone
• Milnacipran
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Oxycodone
• Oxymorphone
• Pentazocine
• Periciazine
• Remifentanil
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Tiotropium
• Tramadol
• Zotepine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Betel Nut

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Asthma, or history of or
• Chronic obstructive pulmonary disease (COPD), or history of or
• Wheezing—Should not be used in patients with these conditions.

• Congestive heart failure, history of or
• Dehydration or
• Heart attack, history of or
• Heart disease, history of or
• Stroke, history of—May cause side effects to become worse.

• Fainting, history of or
• Glaucoma or
• Hypotension (low blood pressure) or
• Seizures, history of or
• Urinary retention (trouble passing urine)—Use with caution. May make these conditions worse.

A doctor or other trained health professional will give you this medicine in a hospital. This medicine is breathed in (inhaled) through the mouth and into the lungs.

This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Your doctor will check you for breathing problems before and after receiving this medicine.

It is very important that your doctor check your progress after you receive the medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it.

This medicine may cause bronchospasm (narrowing of the airways) and may lead to breathing problems. Tell your doctor right away if you have a cough, trouble breathing, tightness in the chest, or wheezing.

Check with your doctor right away if you are having convulsions (seizures), difficulty with breathing, a fast heartbeat, high fever, high or low blood pressure, increased sweating, loss of bladder control, severe muscle stiffness, unusually pale skin, or tiredness. These could be symptoms of a serious condition called neuroleptic malignant syndrome.

Dizziness, lightheadedness, or fainting may occur, especially when you get up suddenly from a lying or sitting position. Getting up slowly may help. If the problem continues or gets worse, check with your doctor.

This medicine may cause blurred vision, dizziness, drowsiness, trouble with thinking, trouble with controlling body movements, or trouble with your vision, which may lead to falls, fractures or other injuries. Make sure you know how you react to this medicine before you drive, use machines, or do other jobs that require you to be alert, well-coordinated, or able to think or see well.

This medicine may add to the effects of alcohol and other CNS depressants (medicine that makes you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever, allergies, or colds, sedatives, tranquilizers, or sleeping medicines, prescription pain medicine or narcotics, medicine for seizures or barbiturates, muscle relaxants, or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above after you receive this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Blurred vision
• confusion
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• seizures
• sweating
• unusual tiredness or weakness

• Inability to sit still
• need to keep moving
• restlessness

• Cough
• decrease in the frequency of urination
• decrease in urine volume
• decreased vision
• difficulty in passing urine (dribbling)
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• eye pain
• fast, pounding, or irregular heartbeat or pulse
• headache
• high fever
• inability to move the eyes
• increased blinking or spasms of the eyelid
• increased sweating
• loss of balance control
• loss of bladder control
• mask-like face
• nausea or vomiting
• nervousness
• noisy breathing
• painful urination
• pounding in the ears
• severe muscle stiffness
• shuffling walk
• slowed movements
• slurred speech
• sticking out of tongue
• tearing of eyes
• tic-like (jerky) movements of the head, face, mouth, and neck
• tightness in the chest
• tiredness
• trembling and shaking of the fingers and hands
• trouble breathing, speaking, or swallowing
• uncontrolled twisting movements of the neck, trunk, arms, or legs
• unusual facial expressions
• unusually pale skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Change in taste
• drowsiness
• loss of taste
• sleepiness or unusual drowsiness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• For breathing in only.
• You will be shown how to use Adasuve (loxapine inhalation powder) right before you take it.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

Adasuve, a typical antipsychotic, is an inhalation powder of loxapine supplied in a single-use, disposable inhaler containing 10 mg of loxapine base. Adasuve is a drug-device combination product.

Active Ingredient: Loxapine (base). Loxapine, a dibenzoxazepine compound, represents a subclass of tricyclic antipsychotic agents, chemically distinct from the thioxanthenes, butyrophenones, and phenothiazines. Chemically, it is 2-Chloro-11-(4-methyl-1-piperazinyl) dibenz [b,f] [1,4] oxazepine.

Adasuve is a single-use, drug-device combination product that provides rapid systemic delivery by inhalation of a thermally-generated aerosol of loxapine. Oral inhalation through the product initiates the controlled rapid heating of a thin film of excipient-free loxapine to form a thermally-generated drug vapor. The vapor condenses into aerosol particles that are dispersed into the airstream created by the patient inhaling through the mouthpiece.

Each product is packaged inside a sealed foil pouch. The product is a white to off-white plastic unit, with a mouthpiece on one end and a pull-tab protruding from the other end.

Removal of a pull-tab from the product renders it ready for use, as indicated by illumination of a green light. After inhalation through the mouthpiece, successful dosing is signaled by the green light turning off.

Under standardized in vitro test conditions, Adasuve, 10 mg delivers 9.1 mg of loxapine out of the mouthpiece.

The efficacy of Adasuve 10 mg in the acute treatment of agitation associated with schizophrenia or bipolar I disorder was established in two short-term (24-hour), randomized, double-blind, placebo-controlled, fixed-dose trials. Study 1 included 344 patients who met DSM-IV criteria for schizophrenia. Study 2 included 314 patients who met DSM-IV criteria for bipolar I disorder, manic or mixed episodes with or without psychotic features.

Patients were judged by the clinical investigators to be clinically agitated, with a level of agitation that met or exceeded a specific severity threshold as measured by the Positive and Negative Syndrome Scale-Excited Component (PEC). The PEC is an investigator-rated instrument consisting of 5 items: poor impulse control, tension, hostility, uncooperativeness, and excitement. Each item is scored on a scale from 1 to 7 (1 = absent, 4 = moderate, 7 = extreme). Thus, the total PEC score can range from 5 to 35. For enrollment in the studies, patients had to have a PEC score of ≥ 14, with at least one individual item score > 4.

Patients whose agitation was related to acute alcohol or drug intoxication were excluded. Patients with clinically significant acute or chronic pulmonary disease (e.g., asthma, COPD, chronic bronchitis, and emphysema) were excluded from the trials [See Contraindications (4)].

The primary efficacy endpoint in both trials was the mean change from baseline in the PEC score, assessed 2 hours following dosing. The key secondary endpoint was the mean Clinical Global Impression Improvement (CGI-I) Scale score at two hours. The CGI-I is an investigator-rated global assessment of symptom improvement, scored on a scale of 1 to 7: 1 = very much improved; 4 = no change from baseline; 7 = very much worse.

In both studies, mean baseline PEC scores were similar in all treatment groups, averaging 17.3 to 17.7 (Table 4), with individual patient scores ranging from 14 to 31, indicating predominantly moderate levels of agitation. The mean baseline Clinical Global Impression Severity Scale (CGI-S) score in both studies was 4 (moderately ill). In Study 2, 69% of patients had a current manic episode, and 31% had a mixed/manic episode.

In Studies 1 and 2, treatment with Adasuve was statistically significantly superior to placebo on the mean change in PEC score at 2 hours (Table 4). In both studies, the effect of Adasuve was apparent at 10 minutes following dosing (Figures 9 and 10).

a Least squares mean for the difference defined as the change from baseline

b Least squares mean for the difference defined as the change from baseline at hour 2 in the drug group minus that in the placebo group.

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

Figures 9 and 10 show the decreases in PEC score at each time point assessed in the trials. In both trials, the decrease in agitation with Adasuve was apparent at each time point tested (10, 20, 30, 45, 60, 90, and 120 minutes post-dose).

Figure 9. Mean Change from Baseline in PEC Score through 2 Hours after a Single Dose in Agitated Patients with Schizophrenia (Study 1)

Figure 10. Mean Change from Baseline in PEC Score through 2 Hours after a Single Dose in Agitated Patients with Bipolar Disorder (Study 2)

The results of the secondary endpoint, CGI-I scores, are shown in Table 5.

a Least squares mean