Levalbuterol

Common Side Effects of Xopenex

You should tell your doctor if any of the following side effects are severe or don't go away:

• Dizziness
• Nervousness
• Headache
• Uncontrollable shaking
• Heartburn
• Vomiting
• Cough
• Weakness
• Fever
• Leg cramps
• Muscle pain
• Diarrhea

Serious Side Effects of Xopenex

You should call your doctor immediately if you experience any of the following serious side effects:

• Chest pain
• Pounding or fast heartbeat
• Hives, itching, or skin rash
• Increased difficulty breathing
• Difficulty swallowing
• Hoarseness
• Swelling of your face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs

XOPENEX®
(pronounced zo-pen-eks)
(levalbuterol hydrochloride) Inhalation Solution 0.31 mg, 0.63 mg, 1.25 mg 3 mL Unit-Dose Vials

For Oral Inhalation Only
XOPENEX Inhalation Solution is only for use with a nebulizer.

Read this Patient Information before you start to use XOPENEX Inhalation Solution and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is XOPENEX Inhalation Solution?

XOPENEX Inhalation Solution is an inhaled prescription medicine used for the treatment or prevention of bronchospasm in people 6 years of age and older.

It is not known if XOPENEX Inhalation Solution is safe and effective in children younger than 6 years of age.

XOPENEX Inhalation Solution is supplied in 3 mL unit-dose vials in three different strengths of levalbulterol (0.31 mg, 0.63 mg, 1.25 mg). The vials do not require dilution before use.

Who should not use XOPENEX Inhalation Solution?

Do not use XOPENEX Inhalation Solution if you are allergic to levalbuterol, racemic albuterol, or any of the ingredients in XOPENEX. See the end of this leaflet for a complete list of ingredients in XOPENEX Inhalation Solution.

What should I tell my doctor before using XOPENEX Inhalation Solution?

Before you use XOPENEX Inhalation Solution, tell your doctor if you have:

• had an allergic reaction to levalbuterol or racemic albuterol
• heart problems
• high blood pressure
• seizures
• diabetes
• thyroid problems
• any other medical conditions
• are pregnant or planning to become pregnant. It is not known if XOPENEX Inhalation Solution will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. It is not known if XOPENEX Inhalation Solution passes into your breast milk. You and your doctor should decide if you will use XOPENEX Inhalation Solution or breastfeed. You should not do both.

Tell your doctor about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. XOPENEX Inhalation Solution may affect the way other medicines work, and other medicines may affect how XOPENEX Inhalation Solution works.

Especially tell your doctor if you take:

• other asthma medicines
• heart medicines
• medicines that increase urination (diuretics)
• antidepressants
• medicine to treat chronic obstructive pulmonary disease (COPD)

Ask your doctor if you are not sure if any of your medicines are the kinds listed above.

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

How should I use XOPENEX Inhalation Solution?

• Read the step-by-step Instructions for Using XOPENEX Inhalation Solution at the end of this leaflet.
• Use XOPENEX Inhalation Solution exactly as your doctor tells you to. Do not change your dose without talking to your doctor first.
• Your doctor will tell you how many times and when to use your XOPENEX Inhalation Solution.
• An adult should help a child use XOPENEX Inhalation Solution.
• Do not use your XOPENEX Inhalation Solution more often than your doctor tells you to.
• Get medical help right away if XOPENEX Inhalation Solution:
  • does not work as well for your asthma symptoms or
  • your asthma symptoms get worse or
  • you need to use your XOPENEX Inhalation Solution more often than usual
• If you also use another medicine by inhalation, you should ask your doctor for instructions on when to use it while you are also using XOPENEX Inhalation Solution.
• Do not mix XOPENEX Inhalation Solution with other medicines in your nebulizer.
• Only use XOPENEX Inhalation Solution if it is colorless. Throw away the XOPENEX Inhalation Solution vial if the liquid medicine is not colorless.
• Do not use XOPENEX Inhalation Solution after the expiration date on the vial.

What are the possible side effects of XOPENEX Inhalation Solution?

XOPENEX Inhalation Solution can cause serious side effects including:

• sudden shortness of breath (bronchospasm). Sudden shortness of breath can happen right away after using XOPENEX Inhalation Solution.
• worsening asthma
• heart problems
• death. If you use too much XOPENEX Inhalation Solution you can have heart or lung problems that can lead to death.
• serious allergic reactions. Call your doctor and stop using XOPENEX Inhalation Solution right away if you have any symptoms of an allergic reaction such as:
  • swelling of the face, throat or tongue
  • hives
  • rash
  • breathing problems
• low potassium levels in your blood

Call your doctor or go to the nearest hospital emergency room right away if you have any of the serious side effects listed above or if you have worsening lung symptoms.

The most common side effects of XOPENEX Inhalation Solution include:

• palpitations
• chest pain
• fast heart rate
• headache
• dizziness
• tremor
• nervousness

Tell your doctor if you have any side effects that bother you or that do not go away.

These are not all the possible side effects of XOPENEX Inhalation Solution. For more information, ask your doctor or pharmacist.

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

How should I store XOPENEX Inhalation Solution?

• Store unopened XOPENEX Inhalation Solution vials in the protective foil pouch they come in between 68°F and 77°F (20°C and 25°C).
• Keep XOPENEX Inhalation Solution away from light and heat.
• When a XOPENEX Inhalation Solution foil pouch is opened, use the vials within 2 weeks.
• When XOPENEX Inhalation Solution vials are removed from the foil pouch, use them right away or within 1 week.

Keep XOPENEX Inhalation Solution and all medicines out of the reach of children.

General information about the safe and effective use of XOPENEX Inhalation Solution.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use XOPENEX Inhalation Solution for a condition for which it was not prescribed. Do not give XOPENEX Inhalation Solution to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about XOPENEX Inhalation Solution. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about XOPENEX Inhalation Solution that is written for health professionals.

For customer service, call 1-888-394-7377.

To report adverse events, call 1-877-737-7226.

For medical information, call 1-800-739-0565.

What are the ingredients in XOPENEX Inhalation Solution?

Active ingredient: levalbuterol hydrochloride

Inactive ingredients: sodium chloride, sulfuric acid, water and nitrogen

Instructions for Using XOPENEX Inhalation Solution

XOPENEX Inhalation Solution vial (see Figure A):

Figure A

Using your XOPENEX Inhalation Solution:

Read the following Steps before using your XOPENEX Inhalation Solution. If you have any questions, ask your doctor or pharmacist.

Step 1. Open the foil pouch by tearing the notched edge along the seam of the pouch (See Figure B). Remove 1 vial to be used right away. Keep the rest of the unused vials in the foil pouch to protect them from light and heat.

Figure B

Step 2. Hold the vial in your hands. Make sure your thumb and finger cover the twist-off tabs below the X-top (See Figure C).

Figure C

Step 3. While holding the top firmly between your thumb and finger, twist the body of the vial to open the vial (See Figure C).

Step 4. Throw away the top of the vial and squeeze the entire contents of the vial into the nebulizer reservoir (See Figure D).

Figure D

Step 5. Connect the nebulizer reservoir to the mouthpiece (See Figure E.1) or face mask (See Figure E.2).

Figure E.1

Figure E.2

Step 6. Connect the nebulizer to the compressor (See Figure F).

Figure F

Step 7. Sit in a comfortable, upright position. Place the mouthpiece in your mouth (See Figure G.1) or put on your face mask (See Figure G.2). Turn on the compressor.

Figure G.1

 Figure G.2

Step 8. Breathe as calmly, deeply, and evenly as possible until no more mist is seen in the nebulizer reservoir. Your treatment will take about 5 to 15 minutes. When you do not see any mist in the nebulizer reservoir, your treatment is finished.

Step 9. Clean and store your nebulizer. See the manufacturer's instructions that come with your nebulizer for how to clean and store your nebulizer.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Levalbuterol may be found in some form under the following brand names:

• Xopenex

• Xopenex HFA

Your pharmacist can provide more information about levalbuterol inhalation.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 6.01. Revision date: 7/12/2012.

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Storage

Oral Inhalation

20–25°C with the actuator in downward position; protect from freezing and direct sunlight.b Do not puncture or incinerate the canister.b Exposure to temperatures >49°C may cause canister to burst.b

20–25°C.216 Store single-use vials in protective foil pouch to protect from light until used.216

Once the foil pouch has been opened, use any vials remaining in the pouch within 2 weeks.216 Use vials removed from the pouch within 1 week.216 Discard vials if the solution becomes discolored.216

Adults and Adolescents ≥ 12 Years Old

The safety and efficacy of Levalbuterol inhalation solution were evaluated in a 4 week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 362 adult and adolescent patients 12 years of age and older, with mild-to-moderate asthma (mean baseline FEV1 60% of predicted). Approximately half of the patients were also receiving inhaled corticosteroids. Patients were randomized to receive Levalbuterol 0.63 mg, Levalbuterol 1.25 mg, racemic albuterol sulfate 1.25 mg, racemic albuterol sulfate 2.5 mg, or placebo three times a day administered via a PARI LC Plus™ nebulizer and a Dura-Neb® portable compressor. Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered-dose inhaler (MDI) was used on an as-needed basis as the rescue medication.

Efficacy, as measured by the mean percent change from baseline FEV1, was demonstrated for all active treatment regimens compared with placebo on day 1 and day 29. On both day 1 (see Figure 1) and day 29 (see Figure 2), 1.25 mg of Levalbuterol demonstrated the largest mean percent change from baseline FEV1 compared with the other active treatments. A dose of 0.63 mg of Levalbuterol and 2.5 mg of racemic albuterol sulfate produced a clinically comparable mean percent change from baseline FEV1 on both day 1 and day 29.

Figure 1: Mean Percent Change from Baseline FEV1 on Day 1, Adults and Adolescents ≥ 12 years old

Figure 2: Mean Percent Change from Baseline FEV1 on Day 29, Adults and Adolescents ≥ 12 years old

The mean time to onset of a 15% increase in FEV1 over baseline for Levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17 minutes and 10 minutes, respectively, and the mean time to peak effect for both doses was approximately 1.5 hours after 4 weeks of treatment. The mean duration of effect, as measured by a > 15% increase from baseline FEV1, was approximately 5 hours after administration of 0.63 mg of Levalbuterol and approximately 6 hours after administration of 1.25 mg of Levalbuterol after 4 weeks of treatment. In some patients, the duration of effect was as long as 8 hours.

Children 6 to 11 Years Old

A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in children with mild-to-moderate asthma (mean baseline FEV1 73% of predicted) (n = 316). Following a 1 week placebo run-in, subjects were randomized to Levalbuterol (0.31 or 0.63 mg), racemic albuterol (1.25 or 2.5 mg), or placebo, which were delivered three times a day for 3 weeks using a PARI LC Plus™ nebulizer and a Dura-Neb® 3000 compressor.

Efficacy, as measured by mean peak percent change from baseline FEV1, was demonstrated for all active treatment regimens compared with placebo on day 1 and day 21. Time profile FEV1 curves for day 1 and day 21 are shown in Figure 3 and Figure 4, respectively. The onset of effect (time to a 15% increase in FEV1 over test-day baseline) and duration of effect (maintenance of a > 15% increase in FEV1 over test-day baseline) of Levalbuterol were clinically comparable to those of racemic albuterol.

Figure 3: Mean Percent Change from Baseline FEV1 on Day 1, Children 6 to 11 Years of Age

Figure 4: Mean Percent Change from Baseline FEV1 on Day 21, Children 6 to 11 Years of Age

Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on heart rate

Absorption

A portion of inhaled dose is absorbed to systemic circulation

Metabolism

Metabolized primarily in the gastrointestinal tract via SULT1A3 (sulfotransferase)

Excretion

Urine (80% to 100%), feces (<20%)

Measured as a 15% increase in FEV1:

Metered-dose inhaler: 5.5 to 10.2 minutes; Peak effect: 76 to 78 minutes

Nebulization solution: 10 to 17 minutes; Peak effect: 1.5 hours

Time to Peak

Nebulization solution: Children: 0.3 to 0.6 hours, Adults: 0.2 hours

Racemic albuterol clearance decreased by 67% in patients with creatinine clearance of 7 to 53 mL/minute.

Inhalation: For oral inhalation only.

Metered-dose inhaler: Shake well before use, avoid spraying in the eyes. Prime with 4 test sprays prior to first use or if inhaler has not been used for more than 3 days. Clean actuator (mouthpiece) weekly with warm water and air dry thoroughly. A spacer device or valved holding chamber is recommended when using a metered-dose inhaler. Each inhaler contains 200 actuations, discard when the display window shows zero.

Nebulization solution: Safety and efficacy were established when administered with the following nebulizers: PARI LC Jet, PARI LC Plus, as well as the following compressors: PARI Master, Dura-Neb 2000, and Dura-Neb 3000. Concentrated solution should be diluted prior to use. Blow-by administration is not recommended, use a mask device if patient unable to hold mouthpiece in mouth for administration.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience rhinorrhea, vomiting, tremors, or pharyngitis. Have patient report immediately to prescriber signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), angina, tachycardia, severe dizziness, passing out, severe anxiety, severe headache, difficulty breathing, wheezing, or cough (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Applies to levalbuterol: inhalation aerosol, inhalation solution

General

This drug has been associated with paradoxical bronchospasm, cardiovascular effects, immediate hypersensitivity reactions, and hypokalemia.[Ref]

Cardiovascular

ECG abnormal, ECG change, hypotension, and syncope occurred in less than 2%.[Ref]

Common (1% to 10%): Hypertension, tachycardia
Frequency not reported: ECG abnormal, ECG change, hypotension, syncope
Postmarketing reports: Arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles)[Ref]

Musculoskeletal

Myalgia occurred in less than 2%.[Ref]

Common (1% to 10%): Leg cramps
Frequency not reported: Myalgia[Ref]

Metabolic

Metabolic acidosis occurred in less than 2%.[Ref]

Frequency not reported: Changes in plasma glucose and serum potassium; metabolic acidosis[Ref]

Nervous system

Central nervous system stimulation and hyperesthesia of the hand occurred in less than 2%.[Ref]

Common (1% to 10%): Dizziness, migraine, tremor, nervousness
Frequency not reported: Central nervous system stimulation, hyperesthesia of the hand[Ref]

Other

Common (1% to 10%): Pain, flu syndrome, accidental injury, asthenia, fever
Frequency not reported: Ear pain, herpes simplex, chills, cyst[Ref]

Ear pain, herpes simplex, chills, and cyst occurred in less than 2%.[Ref]

Gastrointestinal

Diarrhea, dry mouth, dry throat, nausea, gastroenteritis, vomiting, and constipation occurred in less than 2%.

Common (1% to 10%): Dyspepsia
Frequency not reported: Diarrhea, dry mouth, dry throat, nausea, gastroenteritis, vomiting, constipation
Postmarketing reports: Gastroesophageal reflux disease (GERD), nausea

Respiratory

Common (1% to 10%): Asthma, pharyngitis, rhinitis, bronchitis, sinusitis, turbinate edema, cough increased, viral infection
Frequency not reported: Epistaxis, lung disorder, asthma exacerbation, wheezing
Postmarketing reports: Chest pain, dysphonia, dyspnea

Viral infection, epistaxis, lung disorder, asthma exacerbation, and wheezing occurred in less than 2%.

Dermatologic

Frequency not reported: Acne, sweating
Postmarketing reports: Rash, urticaria

Acne and sweating occurred less than 2%.

Hypersensitivity

Common (1% to 10%): Allergic reactions
Postmarketing reports: Angioedema, anaphylaxis

Genitourinary

Frequency not reported: Hematuria, dysmenorrhea, vaginal moniliasis

Hematuria, dysmenorrhea, vaginal moniliasis occurred in less than 2%.

Immunologic

Frequency not reported: Lymphadenopathy

Lymphadenopathy occurred in less than 2%.

Ocular

Eye itch occurred in less than 2%.

Frequency not reported: Eye itch

Psychiatric

Insomnia occurred in less than 2%.

Common (1% to 10%): Anxiety
Frequency not reported: Insomnia

Some side effects of levalbuterol may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Inhalation Aerosol:
Less than 4 years: Not approved
4 years or older:
-2 inhalations (90 mcg) orally every 4 to 6 hours or
-1 inhalation (45 mcg) orally every 4 hours

Inhalation Solution:
Less than 6 years old: Not approved
6 to 11 years:
-Recommended dose: 0.31 mg inhaled orally by nebulization three times a day
-Maximum dose: 0.63 mg inhaled orally three times a day
12 years or older:
-Initial dose: 0.63 mg inhaled orally by nebulization three times a day (every 6 to 8 hours)
-For severe asthma, or if not responding to initial dose: 1.25 mg inhaled orally, by nebulization, three times a day

Comments:
-If higher doses of the inhalation solution are used, monitor closely for adverse systemic effects; evaluate risk and benefit of this dose.
-If a previously effective dosage fails to provide the usual response, it may be a sign of destabilization of asthma; reevaluate the patient and treatment and consider the use of corticosteroids.
-The safety and efficacy of the inhalation solution has not been evaluated when mixed together with other drugs in a nebulizer.
-Recommended dose should not be exceeded.

Uses: Treatment or prevention of bronchospasm in patients with reversible obstructive airway disease; asthma

Administration advice:
-This drug is for oral inhalation only.
Inhalation Solution:
-Administer by nebulization using a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor.
-The safety and efficacy of the inhalation solution have been established only when administered using the PARI LC Jet and PARI LC Plus nebulizers, and the PARI Master Dura-Neb 2000 and Dura-Neb 3000 compressors.
Inhalation Aerosol:
-Avoid spraying in the eyes.
-Prime the inhaler before using for the first time and when it has not been used for more than 3 days by releasing 4 test sprays into the air, away from the face.
-Wash the actuator with warm water and air dry thoroughly at least once a week.

General: This drug is not a substitute for corticosteroids and may not be adequate to control asthma; consider adding a corticosteroid to the treatment with this drug.

Monitoring:
-Signs and symptoms of adverse systemic effects
-Metabolic: Potassium levels

Patient advice:
-Discontinue immediately if hypersensitivity reactions and/or paradoxical bronchospasm occur.
-Excessive use may be fatal; recommended dose should not be exceeded.

Substance Name

Levalbuterol

CAS Registry Number

34391-04-3

Drug Class

Anti-Asthmatic Agents

Bronchodilators

Beta Adrenergic Agonists