Loxapine

Black Box Warnings

Patients with dementia-related psychosis who are treated with antipsychotic drugs are at an increased risk of death as shown in short-term controlled trials. The deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature.

This drug is not approved for the treatment of patients with dementia-related psychosis.

Bronchospasm

• Can cause bronchospasm with potential to lead to respiratory distress and respiratory arrest
• Available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ADASUVE REMS
• Administer only in an enrolled healthcare facility that has immediate access on site to supplies and personnel trained to manage acute bronchospasm, and ready access to emergency response services; facilities must have short-acting bronchodilator, including a nebulizer and inhalation solution, for immediate treatment of bronchospasm

Contraindications

Documented hypersensitivity; severe CNS depression; severe liver or cardiac disease, bone marrow suppression; narrow-angle glaucoma

CNS depression (including coma), neuroleptic malignant syndrome (NMS), poorly controlled seizure disorder

Cautions

Caution in patients with cardiovascular disease or seizures; watch for hypotension if administering IM; in patients taking benzodiazepines, loxapine should be preceded by stopping benzodiazepine therapy for 2 weeks to avoid drug interactions capable of respiratory depression

May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries; perform complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy

FDA Warning regarding off-label use for dementia in elderly

Can cause bronchospasm that has potential to lead to respiratory distress and respiratory arrest (See BBW)

REMS to Mitigate Bronchospasm

• Available only through restricted program under a REMS called the ADASUVE REMS
• Healthcare facilities that dispense and administer therapy must be enrolled and comply with REMS requirements; certified healthcare facilities must be able to provide immediate access on site to supplies and personnel trained to manage acute bronchospasm, and ready access to emergency response services
• Facilities must have a short-acting bronchodilator (e.g., albuterol), including nebulizers and inhalation solutions, for immediate treatment of bronchospasm
• Wholesalers and distributors must distribute only to enrolled healthcare facilities

Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.

Oral:

Common side effects include:

• drowsiness
• dizziness
• faintness
• weakness
• headache
• unusual, slowed, or uncontrollable movements of any part of the body
• restlessness
• numbness, burning, or tingling of the hands or feet

Inhalational:

The most common side effects 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 loxapine. 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.

Tell your healthcare provider if you are breastfeeding or plan to breastfeed. It is not known if loxapine passes into your breast milk. You and your healthcare provider should decide if you will take loxapine if you are breastfeeding.

Oral:

Loxapine comes in the form of a capsule to be taken 2 to 4 times a day, with or without food.

Inhalational

• Loxapine must be administered only by a healthcare professional.
• Your healthcare provider will show you how to take loxapine right before you take it.
• Take loxapine exactly as your healthcare provider shows you to take it.
• Do not drive, operate heavy machinery, or do other dangerous activities until you know how loxapine affects you.
• Do not drink alcohol while taking loxapine. It can increase your chances of getting serious side effects.

• Store loxapine capsules at 20°-25°C (68°-77°F).
• Keep this and all medicines out of the reach of children.

WARNING: BRONCHOSPASM and INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Bronchospasm

Loxapine can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest. Administer loxapine 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 loxapine, screen patients regarding a current diagnosis, history, or symptoms of asthma, COPD and other lung diseases, and examine (including chest auscultation) patients for respiratory signs. Monitor for signs and symptoms of bronchospasm following treatment with loxapine.

Because of the risk of bronchospasm, loxapine is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen 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 between 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 causes 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 may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Loxapine is not approved for the treatment of patients with dementia-related psychosis.

You should not use loxapine if you have decreased alertness caused by taking certain medications or drinking alcohol.

Loxapine is not approved for use in psychotic conditions related to dementia. Loxapine may increase the risk of death in older adults with dementia-related conditions.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include weak or shallow breathing, fainting, or seizure (convulsions).

Take loxapine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

To use the oral liquid:

• Measure the medicine only with the measuring dropper provided.
• Mix the medicine with orange juice or grapefruit juice before drinking.

Dosing

The dose of loxapine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of loxapine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For schizophrenia:
  • For oral dosage form (capsules):
    • Adults—At first, 20 to 50 milligrams (mg) per day, divided and given in two to four doses per day. Your doctor may increase your dose if needed. However, the dose is usually not more than 250 mg per day.
    • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (Loxitane® capsules and solution):
    • Adults—At first, 10 milligrams (mg) 2 times a day. Some patients may need 50 mg per day. Your doctor may increase your dose if needed. However, the dose is usually not more than 250 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of loxapine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Loxapine capsules are contraindicated in comatose or severe drug-induced depressed states (alcohol, barbiturates, narcotics, etc.).

Loxapine is contraindicated in individuals with known hypersensitivity to dibenzoxazepines.

Loxapine Capsules, USP are available containing Loxapine succinate, USP 6.8 mg, 13.6 mg, 34 mg or 68 mg equivalent to 5 mg, 10 mg, 25 mg or 50 mg of Loxapine base, respectively.

The 5 mg capsule is a hard-shell gelatin capsule with an olive opaque cap and an olive opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 7005 in black ink on both the cap and body. They are available as follows:

NDC 0378-7005-01
bottles of 100 capsules

The 10 mg capsule is a hard-shell gelatin capsule with an olive opaque cap and a yellow opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 7010 in black ink on both the cap and body. They are available as follows:

NDC 0378-7010-01
bottles of 100 capsules

The 25 mg capsule is a hard-shell gelatin capsule with an olive opaque cap and a light green opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 7025 in black ink on both the cap and body. They are available as follows:

NDC 0378-7025-01
bottles of 100 capsules

The 50 mg capsule is a hard-shell gelatin capsule with an olive opaque cap and a light blue opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 7050 in black ink on both the cap and body. They are available as follows:

NDC 0378-7050-01
bottles of 100 capsules

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Revised: 3/2017
LOXP:R7

PRINCIPAL DISPLAY PANEL - 5 mg

NDC 0378-7005-01

Loxapine
Capsules, USP
5 mg

Rx only     100 Capsules

Each capsule contains Loxapine
succinate, USP equivalent to
5 mg of Loxapine.

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Usual Dosage: See accompanying
prescribing information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

RM7005A4

PRINCIPAL DISPLAY PANEL - 10 mg

NDC 0378-7010-01

Loxapine
Capsules, USP
10 mg

Rx only      100 Capsules

Each capsule contains Loxapine
succinate, USP equivalent to
10 mg of Loxapine.

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Usual Dosage: See accompanying
prescribing information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

RM7010A4

PRINCIPAL DISPLAY PANEL - 25 mg

NDC 0378-7025-01

Loxapine
Capsules, USP
25 mg

Rx only     100 Capsules

Each capsule contains Loxapine
succinate, USP equivalent to
25 mg of Loxapine.

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Usual Dosage: See accompanying
prescribing information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

RM7025A4

PRINCIPAL DISPLAY PANEL - 50 mg

NDC 0378-7050-01

Loxapine
Capsules, USP
50 mg

Rx only     100 Capsules

Each capsule contains Loxapine
succinate, USP equivalent to
50 mg of Loxapine.

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Usual Dosage: See accompanying
prescribing information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

RM7050A4

Oral, IM: Within 30 minutes; Peak effect: 1.5 to 3 hours

Inhalation: 2 minutes

Oral, IM: ~12 hours

Half-Life Elimination

Biphasic: Oral: Initial: 5 hours; Terminal: 19 hours; Inhalation: 6 to 8 hours

Protein Binding

Inhalation: ~97%

Schizophrenia: IM, Oral: Treatment of schizophrenia.

Agitation associated with schizophrenia or bipolar I disorder: Inhalation: Acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. Note: As part of the Adasuve REMS program to mitigate the risk of bronchospasm, loxapine inhalation must be administered only in an enrolled health care facility.

Psychosis/agitation associated with dementia

Based on the American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia, antipsychotics, such as loxapine, may be considered for the treatment of agitation and psychosis in certain patients with dementia; however, evidence for efficacy is modest and use should be limited to patients whose symptoms are dangerous, severe, or cause significant patient distress due to safety risks associated with antipsychotic use. Additionally, the guidelines recommend giving preference to second generation antipsychotics over first generation antipsychotics like loxapine in elderly patients with dementia-related psychosis due to a potentially greater risk of harm relative to second generation antipsychotics.

Inhalation: No dosage adjustment necessary.

Oral: There are no dosage adjustments provided in the manufacturer’s labeling.

Capsules: Store at 20°C to 25°C (68°F to 77°F).

Inhalation: Store at 15°C to 30°C (59°F to 86°F).

Canadian products: Injection solution, oral solution, tablets: Store at 15°C to 30°C (59°F to 86°F).

Applies to loxapine: oral capsule, oral solution, oral tablet

Other dosage forms:

• inhalation powder

Along with its needed effects, loxapine 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 immediately if any of the following side effects occur while taking loxapine:

• Difficulty with speaking or swallowing
• lip smacking or puckering
• loss of balance control
• mask-like face
• puffing of the cheeks
• rapid or fine, worm-like movements of the tongue
• restlessness or desire to keep moving
• shuffling walk
• slowed movements
• stiffness of the arms and legs
• trembling and shaking of the fingers and hands
• uncontrolled chewing movements
• uncontrolled movements of the arms or legs

• Constipation (severe)
• difficult urination
• inability to move the eyes
• muscle spasms, especially of the neck and back
• skin rash
• twisting movements of the body

• Difficult or fast breathing
• fast heartbeat or irregular pulse
• fever (high)
• high or low blood pressure
• increased blinking or spasms of the eyelid
• increased sweating
• loss of bladder control
• muscle stiffness (severe)
• seizures
• sore throat and fever
• uncontrolled twisting movements of the neck, trunk, arms, or legs
• unusual bleeding or bruising
• unusual facial expressions or body positions
• unusual tiredness or weakness
• unusually pale skin
• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur while taking loxapine:

• Dizziness, faintness, or lightheadedness when suddenly getting up from a lying or sitting position
• drowsiness (severe)
• irregular, fast or slow, or shallow breathing
• loss of consciousness
• muscle trembling, jerking, stiffness, or uncontrolled movements (severe)
• pale or blue lips, fingernails, or skin
• troubled breathing (severe)
• unusual tiredness or weakness (severe)

Some side effects of loxapine 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:

• Blurred vision
• confusion
• dizziness, lightheadedness, or fainting
• drowsiness
• dryness of the mouth

• Constipation (mild)
• decreased sexual ability
• enlargement of the breasts (males and females)
• headache
• increased sensitivity of the skin to sunlight
• missing menstrual periods
• nausea or vomiting
• trouble with sleeping
• unusual secretion of milk
• weight gain

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for Adasuve(R) Inhalation powder. The REMS consists of a communication plan, elements to assure safe use, and an implementation system. Additional information is available at www.fda.gov/REMS.

US BOXED WARNINGS:
INCREASED MORTALITY in ELDERLY PATIENTS with DEMENTIA-RELATED PSYCHOSIS:
-Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an 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 between 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 causes 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 may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Loxapine succinate is not approved for the treatment of patients with dementia-related psychosis.
BRONCHOSPASM:
-This drug can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest. This drug is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Adasuve REMS. Administer 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).

Safety and efficacy have not been established in pediatric patients.

Consult WARNINGS section for additional precautions.

Administration advice:
-Take capsules with or without food

Inhaler:
-Do not administer more than 1 dose within a 24-hour period
-For preparation of inhaler, see below
-Explain to patient that it is normal for the inhaler to produce a flash of light, a clicking sound, and become warm during use.
-To administer dose, patient should breathe out fully to empty the lungs; place mouthpiece between lips, close lips, and inhale with a steady deep breath through the mouthpiece; remove mouthpiece and hold breath as long as possible up to 10 seconds.
-Check that the green light turns off as this will indicate that a dose has been delivered; if the green light remains on, the dose has not been delivered; may repeat administration up to 2 additional times; if still, the green light does not turn off, discard the inhaler and start over with a new one.

Storage requirements:
-Keep inhaler in pouch until ready to use
-The inhaler contains a lithium battery; dispose of in accordance with all federal, state, and local laws.

Preparation techniques:
-Tear open pouch to remove the inhaler; the indicator light should be off.
-Firmly pull the plastic tab from the rear of the inhaler; the green light should turn on indicating the inhaler is ready for use; the inhaler will automatically deactivate if not used within 15 minutes (the green light will turn off and the inhaler is not useable).
-Discard inhaler after 1 use.

General:
-Psychomotor agitation is defined in DSM-IV as "excessive motor activity associated with a feeling of inner tension".
-Patients exposed chronically to antipsychotics should understand the risk of tardive dyskinesia
-During chronic therapy, patients should be periodically reassessed to determine continued need for treatment.

Monitoring:
-Chronic use: Patients with preexisting low WBC and/or a prior history of drug-induced leukopenia or neutropenia should monitor CBC frequently during the first few months.
-For patients using inhaler, monitor for signs and symptoms of bronchospasm at least every 15 minutes and for at least 1 hour after use; monitoring should include chest auscultation.

Patient advice:
-This drug may impair judgment, thinking, or motor skills; have patient avoid driving or operating machinery until adverse effects are determined.
-Advise patient to speak to physician or health care professional if pregnant, intend to become pregnant, or are breastfeeding.
-Patients should be aware of signs and symptoms of neuroleptic malignant syndrome and be instructed to contact health care provider right away if symptoms are present.
-Patients should be advised to report signs/symptoms of bronchospasm (e.g., wheezing, shortness of breath, chest tightness, cough).