Xopenex Inhalation Solution Concentrate

XOPENEX (levalbuterol HCl) Inhalation Solution Concentrate is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

Inhalation Solution Concentrate: 0.5 mL unit-dose vials containing 1.25 mg of levalbuterol that must be diluted before use. Xopenex Inhalation Solution Concentrate is available in cartons of 30 individually pouched vials.

Pregnancy

Teratogenic Effects: Pregnancy Category C.

There are no adequate and well-controlled studies of XOPENEX Inhalation Solution in pregnant women. Because animal reproduction studies are not always predictive of human response, XOPENEX Inhalation Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in newborns of women treated with racemic albuterol, which contains the levalbuterol isomer (active drug substance of XOPENEX Inhalation Solution). However, since multiple medications were taken during some of the pregnancies and there was no consistent pattern of anomalies, it was not possible to establish a relationship between racemic albuterol use and the occurrence of these congenital anomalies.

In animal studies, oral administration of levalbuterol HCl to pregnant New Zealand White rabbits found no evidence of teratogenicity at doses up to 25 mg/kg/day (approximately 108 times the maximum recommended daily inhalation [MRDI] dose of levalbuterol HCl for adults on a mg/m2 basis).

However, other studies demonstrated that racemic albuterol sulfate was teratogenic in mice and rabbits at doses comparable to the human therapeutic range. Pregnant mice administered racemic albuterol sulfate subcutaneously had a dose-related increased incidence of cleft palate in their fetuses (4.5% of fetuses at 0.25 mg/kg/day or greater, corresponding to approximately 0.3 times the MRDI dose, 9.3% of fetuses at 2.5 mg/kg/day, approximately 3 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/ kg/day (approximately 0.03 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis). In addition, oral administration of racemic albuterol sulfate to pregnant rabbits resulted in an increased incidence of cranioschisis in fetuses (approximately 215 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis).

Non-Teratogenic Effects: A study in which pregnant rats were dosed with radiolabeled racemic albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.

Labor and Delivery

Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of XOPENEX Inhalation Solution for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

XOPENEX Inhalation Solution has not been approved for the management of preterm labor. The benefit:risk ratio when levalbuterol HCl is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including racemic albuterol.

Nursing Mothers

Plasma concentrations of levalbuterol after inhalation of therapeutic doses are very low in humans. It is not known whether levalbuterol is excreted in human milk.

Because of the potential for tumorigenicity shown for racemic albuterol in animal studies and the lack of experience with the use of XOPENEX Inhalation Solution by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when XOPENEX Inhalation Solution is administered to a nursing woman.

Pediatric Use

Pediatric Patients 6 Years of Age and Older

The safety and efficacy of XOPENEX Inhalation Solution have been established in pediatric patients 6 years of age and older in an adequate and well-controlled clinical trial [see Adverse Reactions (6) and Clinical Studies (14)].

Pediatric Patients less than 6 Years of Age

XOPENEX Inhalation Solution is not indicated for pediatric patients less than 6 years of age.

Clinical trials with XOPENEX Inhalation Solution in this age group failed to meet the primary efficacy endpoint and demonstrated an increased number of asthma-related adverse reactions following chronic XOPENEX treatment.

XOPENEX Inhalation Solution was studied in 379 pediatric patients less than 6 years of age with asthma or reactive airway disease - (291 patients 2 to 5 years of age, and 88 patients from birth to less than 2 years of age). Efficacy and safety data for XOPENEX Inhalation Solution in this age group are primarily available from one 3-week, multicenter, randomized, double-blind, placebo-controlled study (Study 1) in 211 pediatric patients between the ages of 2 and 5 years, of whom 119 received XOPENEX Inhalation Solution. Over the 3 week treatment period, there were no significant treatment differences in the Pediatric Asthma Questionnaire (PAQ) total score between groups receiving XOPENEX Inhalation Solution 0.31 mg, XOPENEX Inhalation Solution 0.63 mg, racemic albuterol, and placebo. Additional safety data following chronic dosing is available from a 4-week, multicenter, randomized, modified-blind, placebo-controlled study (Study 2) of 196 patients between the ages of birth and 3 years, of whom 63 received open-label XOPENEX Inhalation Solution. In these two studies, treatment-emergent asthma exacerbations or asthma-related adverse reactions and treatment discontinuations due to asthma occurred at a higher frequency in XOPENEX Inhalation-treated subjects compared to control (Table 5). Other adverse reactions were consistent with those observed in the clinical trial population of patients 6 years of age and older [see Adverse Reactions (6.1)].

Geriatric Use

Clinical studies of XOPENEX Inhalation Solution did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Only 5 patients 65 years of age and older were treated with XOPENEX Inhalation Solution in a 4-week clinical study [see Clinical Pharmacology (12) and Clinical Studies (14)] (n=2 for 0.63 mg and n=3 for 1.25 mg). In these patients, bronchodilation was observed after the first dose on day 1 and after 4 weeks of treatment. In general, patients 65 years of age and older should be started at a dose of 0.63 mg of XOPENEX Inhalation Solution. If clinically warranted due to insufficient bronchodilator response, the dose of XOPENEX Inhalation Solution may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratory monitoring, to the maximum recommended daily dose [see Dosage and Administration (2)].

Renal Impairment

Albuterol is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

XOPENEX (levalbuterol HCl) Inhalation Solution Concentrate (foil pouch label color red) is supplied in 0.5 mL unit-dose, low-density polyethylene (LDPE) vials as a clear, colorless, sterile, preservative-free, aqueous solution. Each vial contains 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl) and is available in cartons of 30 (NDC 17478-171-30) individually pouched vials.

XOPENEX Inhalation Solution is also available in 3 mL vials in three different strengths of levalbuterol: 0.31 mg (NDC 17478-172-24), 0.63 mg (NDC 17478-173-24), and 1.25 mg (NDC 17478-174-24).

Store Xopenex Inhalation Solution Concentrate in the protective foil pouch at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light and excessive heat. Open the foil pouch just prior to administration. Once the foil pouch is opened, the contents of the vial should be used immediately. Discard any vial if the solution is not colorless.

Dilute XOPENEX (levalbuterol HCl) Inhalation Solution Concentrate with sterile normal saline before administration by nebulization.

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Use this medicine regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Avoid situations that may make your condition worse such as exercising in cold, dry air; smoking; breathing in dust; and exposure to allergens such as pet fur.

Applies to levalbuterol: inhalation aerosol powder, inhalation solution

Along with its needed effects, levalbuterol (the active ingredient contained in Xopenex Concentrate) 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 levalbuterol:

• Fast heartbeat

• Chest pain or tightness
• dizziness
• feeling “faint”
• lightheadedness
• troubled breathing

• Cough
• difficult or labored breathing
• difficulty swallowing
• extra heartbeats
• fainting
• fast, pounding, slow, or irregular heartbeat or pulse
• hives, welts, itching, or rash
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• noisy breathing
• redness of the skin
• tightness in the chest
• unusual tiredness or weakness

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

• Chest pain
• dizziness
• dry mouth
• general feeling of discomfort or illness
• headache
• impaired consciousness
• irregular or fast heartbeat
• lightheadedness
• nausea
• nervousness
• seizures
• sleeplessness
• sweating
• tremor

Some side effects of levalbuterol 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:

• Accidental injury (in children 4 to 11 years of age)
• anxiety
• body aches or pain
• chills
• congestion
• cough or hoarseness
• dryness or soreness of the throat
• fever
• general aches and pains
• headache
• hoarseness
• increased cough
• leg cramps
• loss of appetite
• migraines or other headaches
• muscle tightness
• nervousness
• runny or stuffy nose

• Abdominal or stomach pain
• abnormal growth filled with fluid or semisolid material
• blemishes on the skin
• blood in the urine
• bloody nose
• burning, dry, or itching eyes
• burning or stinging of the skin
• cough producing mucus
• cramps
• diarrhea
• difficulty having a bowel movement (stool)
• discharge from the eye
• dry mouth or throat
• ear pain
• excessive tearing
• eye itch
• heavy menstrual bleeding
• muscle pain
• night sweats
• numbness or decreased sensitivity of the hand
• pain
• painful cold sores or blisters on the lips, nose, eyes, or genitals
• pimples
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• tingling sensation in the arms or legs
• vaginal yeast infection
• weight loss

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